Materiały źródłowe

• #1 Raynaud Syndrome – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/peripheral-arterial-disorders/raynaud-syndrome

  Raynaud syndrome is probably due to an exaggerated alpha-2 adrenergic response that triggers vasospasm; the mechanism is not defined. […] Raynaud syndrome may accompany migraine headaches, variant angina, and pulmonary hypertension, suggesting that these disorders share a common vasospastic mechanism. […] Raynaud syndrome secondary to a connective tissue disorder may progress to painful digital gangrene; Raynaud syndrome secondary to systemic sclerosis tends to cause extremely painful, infected ulcers on the fingertips. […] Cervical or local sympathectomy is controversial; it is reserved for patients with progressive disability unresponsive to all other measures, including treatment of underlying disorders. Sympathectomy often abolishes the symptoms, but relief may last only 1 to 2 years.

• #2 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In Raynaud phenomenon, blood-flow restriction occurs during cold temperatures and emotional stress. Specifically, in Raynaud phenomenon, there is vasoconstriction of the digital arteries and cutaneous arterioles. Overall, Raynaud phenomenon is a transient and peripheral vasoconstrictive response to cold temperatures or emotional stress. […] Three mechanisms contribute to Raynaud phenomena. These are decreased blood flow, blood vessels constriction, neurogenic responses, and inflammatory and immune responses. […] With cold temperatures, the sympathetic nervous system causes the release of vasoconstricting neuropeptides and norepinephrine leading to vasoconstriction of arteriole smooth muscle and decreased blood flood to the skin. Of note, in secondary Raynaud phenomena, endothelin-1 is released by endothelial cells which causes vasoconstriction.

• #3 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  Raynauds phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. […] The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. […] In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. […] The complex pathogenesis of RP remains incompletely understood. […] Primary and secondary RP likely follow distinct pathogenetic pathways. […] In primary RP, vascular abnormalities are primarily functional, while secondary RP exhibits both structural and functional impairments. […] Endothelial dysfunction, a key factor in secondary RP, particularly SSc, disrupts the endotheliums normal function.

• #4 (PDF) Raynaud’s phenomenon: Pathogenesis and management

  https://www.academia.edu/10575219/Raynauds_phenomenon_Pathogenesis_and_management

  Raynaud’s phenomenon is a common clinical disorder for which patients frequently seek the expertise and care of dermatologists. […] Despite more than 140 years of research, the pathophysiology of Raynaud’s phenomenon continues to elude investigators. […] Recently, there has been renewed interest in finding the pathogenetic mechanisms of Raynaud’s phenomenon, an effort that has led to more potential targeted therapeutics. […] The pathogenesis of systemic sclerosis is not fully understood and a comprehensive discussion is beyond the scope of this article; however, a brief review of the vascular abnormalities is pertinent to demonstrate that structure and function are interdependent in Raynaud’s phenomenon secondary to systemic sclerosis. […] In patients with Raynaud’s disease secondary to systemic sclerosis, there was also an aggravation of vasoconstriction on cooling to 318C that, compared with healthy control subjects, was associated with a significantly greater increase in tyrosine phosphorylation.

• #5

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Raynauds phenomenon manifests as episodic vasospasm leading to acral vascular compromise following emotional stress or exposure to a cold environment. […] The distinction between Raynauds disease and secondary Raynauds phenomenon is of utmost importance because of differences in pathophysiology and hence natural course, prognosis, complications, associations, and treatment. […] Pathogenesis underlying Raynauds phenomenon had not yet been properly elucidated. Initially, Raynaud hypothesized that these vasospastic episodes develop secondary to irritability of the spinal cord affecting vascular innervation. Around 70 years later, Lewis and Pickering suggested that local effects cause vascular spasms, not CNS abnormalities. […] Multiple factors including mediators released by blood cells, blood vessels, hormones, and probably neuronal factors control blood vessel reactivity. Herrick divided pathophysiological mechanisms into three major parts, abnormalities in vessels, abnormalities in the nervous system, and abnormalities within the vessels.

• #6 Pathogenesis of Raynaud’s phenomenon – PubMed

  https://pubmed.ncbi.nlm.nih.gov/15741200/

  The pathogenesis of Raynaud’s phenomenon is not fully understood. However, the last 20 yr have witnessed enormous increases in our understanding of different mechanisms which, singly or in combination, may contribute. A key point is that Raynaud’s phenomenon can be either primary (idiopathic) or secondary to a number of underlying conditions, and that the pathogenesis and pathophysiology vary between these conditions. […] In this review, I shall discuss the main mechanisms thought to be important in pathophysiology under the three broad headings of 'vascular’, 'neural’ and 'intravascular’. While these are false distinctions because all interrelate, they facilitate discussion of the key elements: the blood vessel wall (particularly the endothelium), the neural control of vascular tone, and the many circulating factors which can impair blood flow and/or cause endothelial injury. Vascular abnormalities include those of both structure and function. Neural abnormalities include deficiency of the vasodilator calcitonin gene-related peptide (released from sensory afferents), alpha(2)-adrenoreceptor activation (possibly with up-regulation of the normally 'silent’ alpha(2C)-adrenoreceptor) and a central nervous system component. Intravascular abnormalities include platelet activation, impaired fibrinolysis, increased viscosity and probably oxidant stress. As our understanding of the pathophysiology of Raynaud’s phenomenon increases, so do our possibilities for identifying effective treatments.

• #7 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In Raynaud phenomenon, blood-flow restriction occurs during cold temperatures and emotional stress. Specifically, in Raynaud phenomenon, there is vasoconstriction of the digital arteries and cutaneous arterioles. Overall, Raynaud phenomenon is a transient and peripheral vasoconstrictive response to cold temperatures or emotional stress. […] Three mechanisms contribute to Raynaud phenomena. These are decreased blood flow, blood vessels constriction, neurogenic responses, and inflammatory and immune responses. […] With cold temperatures, the sympathetic nervous system causes the release of vasoconstricting neuropeptides and norepinephrine leading to vasoconstriction of arteriole smooth muscle and decreased blood flood to the skin. Of note, in secondary Raynaud phenomena, endothelin-1 is released by endothelial cells which causes vasoconstriction.

• #8 Patient education: Raynaud phenomenon (Beyond the Basics) – UpToDate

  https://www.uptodate.com/contents/raynaud-phenomenon-beyond-the-basics/print

  The Raynaud phenomenon (RP) is a condition in which some of the body’s blood vessels (most commonly those in the fingers and toes) constrict in an exaggerated way in response to cold or emotional stress. […] In people with RP, the mechanisms that control vasoconstriction are thought to be altered or defective. The vessels constrict in an exaggerated way in response to cold and emotional or physical stress, causing what is called “Raynaud’s phenomenon” or a Raynaud’s attack. […] The normal control of blood vessel responses to cold and other stimuli is complex, involving the central nervous system, peripheral sensory nerves, and molecules released by circulating cells or from the inner lining of the blood vessel itself (called the endothelium). Raynaud phenomenon (RP) occurs when this complex and delicate system of control is disrupted, which alters the normal responses to the environment.

• #9 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In primary Raynaud phenomenon, an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels results in the vasoconstrictive response to cold temperatures and emotional stress. […] In secondary Raynaud phenomenon, the underlying disease is the factor that disrupts normal vessel reactivity to cold temperatures. Usually, the endothelial function of the digital and cutaneous vessels is compromised leading to eventual vasoconstriction with resulting tissue ischemia. For instance, fibrosis of the vascular system in systemic scleroderma leads to endothelial dysfunction followed by tissue ischemia.

• #10 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  Raynauds phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. […] The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. […] In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. […] The complex pathogenesis of RP remains incompletely understood. […] Primary and secondary RP likely follow distinct pathogenetic pathways. […] In primary RP, vascular abnormalities are primarily functional, while secondary RP exhibits both structural and functional impairments. […] Endothelial dysfunction, a key factor in secondary RP, particularly SSc, disrupts the endotheliums normal function.

• #11 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The vasospasm in primary RP is reversible, while the secondary Raynauds phenomenon in systemic sclerosis is associated with endothelial injury and subsequent structural abnormalities that lead to tissue damage. […] Adrenergic alpha-2 receptors that are more important than alpha-1 receptors in the control of vasoconstriction of digital arteries are suggested to be abnormal in RP. The receptor subtype alpha-2c is found to predominate in the vascular smooth muscle cells of distal cutaneous vessels. […] The endothelium controls blood vessel tone via production of vasodilators (nitric oxide (NO), prostacyclin) and vasoconstrictors (endothelin-1, angiotensin). Endothelial damage in secondary RP in SSc leads to disbalance between vasodilators and vasoconstrictors. […] In SSc, endothelial injury represents a key pathogenic step that mediates the processes of inflammation, thrombus formation, and fibrosis.

• #12 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, an increased production of platelet thromboxane A2, and an impaired fibrolytic system. […] Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #13 Researchers find genetic cause of Raynaud’s phenomenon – Queen Mary University of London

  https://www.qmul.ac.uk/media/news/2023/smd/researchers-find-genetic-cause-of-raynauds-phenomenon-.html

  Researchers at Queen Mary University of Londons Precision Healthcare Research Institute (PHURI) and the Berlin Institute of Health (BIH) at Charit Universittsmedizin Berlin have identified the genetic causes of Raynauds phenomenon. […] Raynauds phenomenon (RP) is a heritable condition that affects blood circulation. Its a vasospastic condition, which means that small blood vessels near the surface of the skin have spasms that can limit blood flow. […] A better understanding of the underlying genetic mechanisms that cause RD is needed to develop safe and effective treatments. […] The researchers discovered variation in two genes that predisposed participants to Raynaud’s phenomenon: One was the alpha-2A-adrenergic receptor for adrenaline, ADRA2A, a classic stress receptor that causes the small blood vessels to contract.

• #14 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Raynauds phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. […] We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p9.61027) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.121.22, p4.81013) as candidate causal genes through integration of gene expression in disease relevant tissues. […] Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of 2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms. […] We highlight two independent disease mechanisms supported by those loci that challenge and advance our current understanding of primary RP, with ADRA2A highlighting the role of 2A-adrenoreceptors and IRX1 as a putative regulator of vasodilation by altering prostaglandin and/or bradykinin responsiveness.

• #15 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In primary Raynaud phenomenon, an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels results in the vasoconstrictive response to cold temperatures and emotional stress. […] In secondary Raynaud phenomenon, the underlying disease is the factor that disrupts normal vessel reactivity to cold temperatures. Usually, the endothelial function of the digital and cutaneous vessels is compromised leading to eventual vasoconstriction with resulting tissue ischemia. For instance, fibrosis of the vascular system in systemic scleroderma leads to endothelial dysfunction followed by tissue ischemia.

• #16 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes that usually occurs in response to cold exposure or stress. […] The pathogenesis involves disruption of the balance between vasoconstriction and vasodilation, with complex interactions between the vascular wall, nerves, hormones, and humoral factors. […] A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon. […] In addition, endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon. […] Angiotensin has vasoconstrictive and profibrotic effects. […] In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.

• #17 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  While primary RP is related to functional alterations alone, in RP secondary to SSc, structural alterations of the vascular wall are also found. […] Hyperactivity of the 2-adrenoceptor and alteration in the production of neuropeptides (e.g. calcitonin gene-related peptide), are some of the mechanisms involved in the vasospasm episodes induced by cold in primary and secondary RP. […] In RP, especially when secondary to SSc, endothelial lesion and activation cause an imbalance between the production of vasoconstrictors and vasodilatory mediators, with an increase in the production of endothelin-1 (powerful vasoconstrictor) and a decrease in the production of NO and prostacyclin (vasodilating agents). […] Besides the functional and contractile alterations, structural alterations are found in secondary RP, mainly in SSc. Proliferation and intimal fibrosis of the small arteries and arterioles result in decrease of vessel lumen; these alterations cause decrease of blood flow and lead to a state of chronic ischemia of the involved organs.

• #18 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The vasospasm in primary RP is reversible, while the secondary Raynauds phenomenon in systemic sclerosis is associated with endothelial injury and subsequent structural abnormalities that lead to tissue damage. […] Adrenergic alpha-2 receptors that are more important than alpha-1 receptors in the control of vasoconstriction of digital arteries are suggested to be abnormal in RP. The receptor subtype alpha-2c is found to predominate in the vascular smooth muscle cells of distal cutaneous vessels. […] The endothelium controls blood vessel tone via production of vasodilators (nitric oxide (NO), prostacyclin) and vasoconstrictors (endothelin-1, angiotensin). Endothelial damage in secondary RP in SSc leads to disbalance between vasodilators and vasoconstrictors. […] In SSc, endothelial injury represents a key pathogenic step that mediates the processes of inflammation, thrombus formation, and fibrosis.

• #19 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes that usually occurs in response to cold exposure or stress. […] The pathogenesis involves disruption of the balance between vasoconstriction and vasodilation, with complex interactions between the vascular wall, nerves, hormones, and humoral factors. […] A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon. […] In addition, endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon. […] Angiotensin has vasoconstrictive and profibrotic effects. […] In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.

• #20 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes that usually occurs in response to cold exposure or stress. […] The pathogenesis involves disruption of the balance between vasoconstriction and vasodilation, with complex interactions between the vascular wall, nerves, hormones, and humoral factors. […] A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon. […] In addition, endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon. […] Angiotensin has vasoconstrictive and profibrotic effects. […] In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.

• #21

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  In Raynauds disease, the vascular abnormality is mostly functional while in secondary cases, the abnormality is both structural and functional leading to compromise in vascularity. […] Endothelial dysfunction- Disturbance of homeostasis of endothelial cells may cause vasoconstriction. […] A deficiency of nitric oxide (NO), a vasodilator may also be a contributory factor. […] In systemic sclerosis cases, fibrotic intimal proliferation and minimal proliferation of tunica media of vessels have been observed. […] Concurrent with intimal proliferation and because of anti-endothelial cell antibodies, there is endothelial cell damage as well. […] The tone of cutaneous vessels is adjusted by the transmitters released by sensory and autonomic nerves. In Raynauds case, vasoconstriction is mediated by neuropeptide dysregulation and 2-adrenoreceptors upregulation.

• #22 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes that usually occurs in response to cold exposure or stress. […] The pathogenesis involves disruption of the balance between vasoconstriction and vasodilation, with complex interactions between the vascular wall, nerves, hormones, and humoral factors. […] A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon. […] In addition, endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon. […] Angiotensin has vasoconstrictive and profibrotic effects. […] In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.

• #23 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In Raynaud phenomenon, blood-flow restriction occurs during cold temperatures and emotional stress. Specifically, in Raynaud phenomenon, there is vasoconstriction of the digital arteries and cutaneous arterioles. Overall, Raynaud phenomenon is a transient and peripheral vasoconstrictive response to cold temperatures or emotional stress. […] Three mechanisms contribute to Raynaud phenomena. These are decreased blood flow, blood vessels constriction, neurogenic responses, and inflammatory and immune responses. […] With cold temperatures, the sympathetic nervous system causes the release of vasoconstricting neuropeptides and norepinephrine leading to vasoconstriction of arteriole smooth muscle and decreased blood flood to the skin. Of note, in secondary Raynaud phenomena, endothelin-1 is released by endothelial cells which causes vasoconstriction.

• #24 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes that usually occurs in response to cold exposure or stress. […] The pathogenesis involves disruption of the balance between vasoconstriction and vasodilation, with complex interactions between the vascular wall, nerves, hormones, and humoral factors. […] A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon. […] In addition, endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon. […] Angiotensin has vasoconstrictive and profibrotic effects. […] In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.

• #25 (PDF) Raynaud’s phenomenon: Pathogenesis and management

  https://www.academia.edu/10575219/Raynauds_phenomenon_Pathogenesis_and_management

  Although impaired fibrinolysis might not be central to the pathogenesis of Raynaud’s phenomenon, it probably contributes to vascular obstruction in a subset of patients with systemic sclerosis. […] Vasodilatory prostaglandins ameliorate Raynaud’s phenomenon secondary to systemic sclerosis. […] The mechanisms that lead to impaired cutaneous vascular tone are complex. […] The regulation of cutaneous vasoconstriction and vasodilation involves altered sympathetic nerve activity and a host of neuronal regulators, including adrenergic and non-adrenergic, as well as REDOX signalling and other signalling such as the RhoA/ROCK pathway. […] The role of nitric oxide in the development of this phenomenon is still complex. […] Impaired vasodilation, increased vasoconstriction, and several intravascular abnormalities have been documented as potential contributors to the development of this disorder.

• #26 Pediatric Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1355650-overview

  The pathophysiology of Raynaud phenomenon is not completely understood; the vasospasm that occurs in the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts involves both central and peripheral mechanisms. […] The pathophysiology of secondary Raynaud phenomenon also involves structural changes to the vasculature that worsens the severity of the Raynaud phenomenon. […] Raynaud phenomenon can be thought of as an exaggerated normal response to cold and emotional stress. […] Primary Raynaud phenomenon rarely affects the nutritive flow, whereas secondary Raynaud phenomenon can cause digital artery vasospasm severe enough to block the nutritive flow, leading to tissue hypoxia and ischemia. […] Structural vascular defects in patients with secondary Raynaud phenomenon who have systemic sclerosis include endothelial cell apoptosis (due to repeated ischemia and antiendothelial cell antibodies), upregulation of adhesion molecules, formation of fibrous intimal lesions, intimal proliferation, capillary enlargement and atrophy, obliteration of vessel patency by perivascular fibrosis or thrombus formation, and defective vascular remodeling and arteriogenesis. […] Functional vascular defects include impaired endothelial-dependent vasodilation, decreased production of vasodilator substances (increased production of endothelial nitric oxide synthetase inhibitor), and increased production of vasoconstrictors such as endothelin-1 and angiotensin II in systemic sclerosis patients.

• #27

  https://link.springer.com/article/10.1007/BF00053426

  The pathogenetic theories and treatment of Raynaud’s phenomenon are reviewed. In primary Raynaud’s disease, most evidence supports a local defect at the digital artery level, with vasoconstriction or vasospasm of the digital arteries inducing the color changes. […] Normal sympathetic activity, low transmural arterial distending forces, and serotonin may be associated factors in the production of vasospastic attacks. […] In Raynaud’s phenomenon, persistent vasoconstriction, thickened vessel walls, increased blood viscosity, and low digital artery blood pressure distal to obstructions may lead to vasospastic attacks with normal sympathetic nerve stimuli. […] Since the underlying cause of primary Raynaud’s disease is unknown, treatment involves the use of agents to reduce sympathetic nerve activity or to prevent vascular smooth muscle contraction.

• #28 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  The neural pathogenic mechanism may originate from cold-induced increased sympathetic tone or, in some cases, peripheral nerve compression. […] Regarding intravascular factors, both primary and secondary RP involve platelet activation and the subsequent release of vasoactive substances like thromboxane and serotonin, which further promote platelet aggregation. […] Impaired erythrocyte flexibility and increased blood viscosity in RP contribute to the rationale for using rheologic drugs like pentoxifylline to improve blood flow. […] A summary of the factors involved in RP pathogenesis is presented in Fig. 1.

• #29

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Stress-induced Raynauds phenomenon suggests the involvement of our nervous system in its pathophysiology. […] In Raynauds patients, calcitonin gene-related peptide (vasodilatory) release from neurons supplying vessels is diminished. […] The ability of sympathetic nerves to get stimulated to cause vasoconstriction on the cooling of the body is augmented in Raynauds patients. […] Various intravascular circulatory factors might cause/exacerbate Raynauds phenomenon, especially in secondary cases. […] Platelet activation and aggregation has been noticed in Raynauds cases. […] Recurrent episodes of vasospasm lead to reperfusion injury of endothelial cells by augmenting the production of reactive oxygen species. […] Other factors like estrogen and genetics might play a role.

• #30 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In Raynaud phenomenon, blood-flow restriction occurs during cold temperatures and emotional stress. Specifically, in Raynaud phenomenon, there is vasoconstriction of the digital arteries and cutaneous arterioles. Overall, Raynaud phenomenon is a transient and peripheral vasoconstrictive response to cold temperatures or emotional stress. […] Three mechanisms contribute to Raynaud phenomena. These are decreased blood flow, blood vessels constriction, neurogenic responses, and inflammatory and immune responses. […] With cold temperatures, the sympathetic nervous system causes the release of vasoconstricting neuropeptides and norepinephrine leading to vasoconstriction of arteriole smooth muscle and decreased blood flood to the skin. Of note, in secondary Raynaud phenomena, endothelin-1 is released by endothelial cells which causes vasoconstriction.

• #31

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Stress-induced Raynauds phenomenon suggests the involvement of our nervous system in its pathophysiology. […] In Raynauds patients, calcitonin gene-related peptide (vasodilatory) release from neurons supplying vessels is diminished. […] The ability of sympathetic nerves to get stimulated to cause vasoconstriction on the cooling of the body is augmented in Raynauds patients. […] Various intravascular circulatory factors might cause/exacerbate Raynauds phenomenon, especially in secondary cases. […] Platelet activation and aggregation has been noticed in Raynauds cases. […] Recurrent episodes of vasospasm lead to reperfusion injury of endothelial cells by augmenting the production of reactive oxygen species. […] Other factors like estrogen and genetics might play a role.

• #32 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The role of endothelin-1 in pathogenesis of primary RP has also been implicated in some studies, but the evidence is weaker in comparison with SSc. […] Calcitonin gene-related peptide (CGRP) is a neuropeptide and a potent vasodilator produced by peripheral sensory nerves. In RP (primary and secondary RP in SSc), especially the secondary forms in SSc, a reduction in the number of CGRP immunoreactive neurons in the skin was found.

• #33 Pediatric Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1355650-overview

  Raynaud phenomenon is thought to be a polygenic phenomenon. […] A genome screen in 6 extended families with multiple cases of Raynaud phenomenon identified 3 potential genes associated with primary Raynaud phenomenon. […] Intravascular defects associated with Raynaud phenomenon include the following: Platelet activation – Present in both primary Raynaud phenomenon and secondary Raynaud phenomenon; leads to increased levels of the vasoconstrictors thromboxane A2 and serotonin and other substances that can contribute to inflammation or angiogenesis such as platelet microparticles and platelet-derived growth factor. […] Defective fibrinolysis – Found in patients with secondary Raynaud phenomenon; can lead to fibrin deposition and obstruction of vasculature. […] Raynaud phenomenon patients also show impairments in neural regulation of vascular tone. […] Both primary Raynaud phenomenon and secondary Raynaud phenomenon patients have decreased levels of calcitonin generelated peptide (CGRP), a potent vasodilator released from sensory afferents.

• #34 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, an increased production of platelet thromboxane A2, and an impaired fibrolytic system. […] Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #35 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  The neural pathogenic mechanism may originate from cold-induced increased sympathetic tone or, in some cases, peripheral nerve compression. […] Regarding intravascular factors, both primary and secondary RP involve platelet activation and the subsequent release of vasoactive substances like thromboxane and serotonin, which further promote platelet aggregation. […] Impaired erythrocyte flexibility and increased blood viscosity in RP contribute to the rationale for using rheologic drugs like pentoxifylline to improve blood flow. […] A summary of the factors involved in RP pathogenesis is presented in Fig. 1.

• #36 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, an increased production of platelet thromboxane A2, and an impaired fibrolytic system. […] Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #37 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, an increased production of platelet thromboxane A2, and an impaired fibrolytic system. […] Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #38

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Stress-induced Raynauds phenomenon suggests the involvement of our nervous system in its pathophysiology. […] In Raynauds patients, calcitonin gene-related peptide (vasodilatory) release from neurons supplying vessels is diminished. […] The ability of sympathetic nerves to get stimulated to cause vasoconstriction on the cooling of the body is augmented in Raynauds patients. […] Various intravascular circulatory factors might cause/exacerbate Raynauds phenomenon, especially in secondary cases. […] Platelet activation and aggregation has been noticed in Raynauds cases. […] Recurrent episodes of vasospasm lead to reperfusion injury of endothelial cells by augmenting the production of reactive oxygen species. […] Other factors like estrogen and genetics might play a role.

• #39 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, an increased production of platelet thromboxane A2, and an impaired fibrolytic system. […] Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #40 Pediatric Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1355650-overview

  Raynaud phenomenon is thought to be a polygenic phenomenon. […] A genome screen in 6 extended families with multiple cases of Raynaud phenomenon identified 3 potential genes associated with primary Raynaud phenomenon. […] Intravascular defects associated with Raynaud phenomenon include the following: Platelet activation – Present in both primary Raynaud phenomenon and secondary Raynaud phenomenon; leads to increased levels of the vasoconstrictors thromboxane A2 and serotonin and other substances that can contribute to inflammation or angiogenesis such as platelet microparticles and platelet-derived growth factor. […] Defective fibrinolysis – Found in patients with secondary Raynaud phenomenon; can lead to fibrin deposition and obstruction of vasculature. […] Raynaud phenomenon patients also show impairments in neural regulation of vascular tone. […] Both primary Raynaud phenomenon and secondary Raynaud phenomenon patients have decreased levels of calcitonin generelated peptide (CGRP), a potent vasodilator released from sensory afferents.

• #41 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  The neural pathogenic mechanism may originate from cold-induced increased sympathetic tone or, in some cases, peripheral nerve compression. […] Regarding intravascular factors, both primary and secondary RP involve platelet activation and the subsequent release of vasoactive substances like thromboxane and serotonin, which further promote platelet aggregation. […] Impaired erythrocyte flexibility and increased blood viscosity in RP contribute to the rationale for using rheologic drugs like pentoxifylline to improve blood flow. […] A summary of the factors involved in RP pathogenesis is presented in Fig. 1.

• #42 (PDF) Raynaud’s phenomenon: Pathogenesis and management

  https://www.academia.edu/10575219/Raynauds_phenomenon_Pathogenesis_and_management

  Although impaired fibrinolysis might not be central to the pathogenesis of Raynaud’s phenomenon, it probably contributes to vascular obstruction in a subset of patients with systemic sclerosis. […] Vasodilatory prostaglandins ameliorate Raynaud’s phenomenon secondary to systemic sclerosis. […] The mechanisms that lead to impaired cutaneous vascular tone are complex. […] The regulation of cutaneous vasoconstriction and vasodilation involves altered sympathetic nerve activity and a host of neuronal regulators, including adrenergic and non-adrenergic, as well as REDOX signalling and other signalling such as the RhoA/ROCK pathway. […] The role of nitric oxide in the development of this phenomenon is still complex. […] Impaired vasodilation, increased vasoconstriction, and several intravascular abnormalities have been documented as potential contributors to the development of this disorder.

• #43 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, an increased production of platelet thromboxane A2, and an impaired fibrolytic system. […] Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #44 Raynaud’s Phenomenon – Life Extension

  https://www.lifeextension.com/protocols/heart-circulatory/raynauds-phenomenon?srsltid=AfmBOopCu2Ho1xjGBpE2n0061qg7BrVd4CLzDD3w8Y7b8ieykWzR2o82

  Oxidative stress is implicated not only in the pathogenesis of Raynauds phenomenon, but can be a significant consequence of the ischemia-reperfusion characteristic of both the primary and secondary forms of this disease as well. Lack of blood flow (ischemia), and its subsequent return (reperfusion), generates free radicals, which can damage the delicate interior lining of the blood vessels, called the endothelium, in the affected tissues; in severe cases this may lead to ulcers and tissue death. Therefore, antioxidants, which neutralize free radicals, have received significant attention among researchers studying Raynauds phenomenon. […] A key feature of secondary Raynauds phenomenon is a disruption of the vasodilation/vasoconstriction equilibrium, resulting in decreased vasodilation and increased vasoconstriction. This appears to be a consequence of decreased production of chemicals that dilate blood vessels, combined with the increased production of chemicals that constrict them.

• #45

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  In Raynauds disease, the vascular abnormality is mostly functional while in secondary cases, the abnormality is both structural and functional leading to compromise in vascularity. […] Endothelial dysfunction- Disturbance of homeostasis of endothelial cells may cause vasoconstriction. […] A deficiency of nitric oxide (NO), a vasodilator may also be a contributory factor. […] In systemic sclerosis cases, fibrotic intimal proliferation and minimal proliferation of tunica media of vessels have been observed. […] Concurrent with intimal proliferation and because of anti-endothelial cell antibodies, there is endothelial cell damage as well. […] The tone of cutaneous vessels is adjusted by the transmitters released by sensory and autonomic nerves. In Raynauds case, vasoconstriction is mediated by neuropeptide dysregulation and 2-adrenoreceptors upregulation.

• #46 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  Raynauds phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. […] The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. […] In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. […] The complex pathogenesis of RP remains incompletely understood. […] Primary and secondary RP likely follow distinct pathogenetic pathways. […] In primary RP, vascular abnormalities are primarily functional, while secondary RP exhibits both structural and functional impairments. […] Endothelial dysfunction, a key factor in secondary RP, particularly SSc, disrupts the endotheliums normal function.

• #47 Raynaud’s phenomenon — the clinical picture, treatment and diagnostics | Walecka | Acta Angiologica

  https://journals.viamedica.pl/acta_angiologica/article/view/AA.2017.0003/44433

  Raynauds disease primary Raynauds phenomenon […] Raynauds disease is a relatively rare phenomenon, affecting 510% of the population worldwide. The incidence may vary depending on the patients gender (1% of men, 20% of women) or climate. It is a vasomotor disorder of small vessels of acral parts of the body, where a sudden pallor is observed. This symptom is symmetrical, however, it may present with varying severity in different locations. The aberration of blood flow caused by the sudden vasospasm of small vessels is not severe enough to cause necrosis or other trophic lesions due to limited blood supply. As Raynauds disease is only a functional disorder, no structural changes of the vessel wall are present. Comparing with the secondary Raynauds syndrome, the vasospasm in Raynauds disease is relatively rare, less severe and patients usually lack anti-nuclear antibodies ANA (or the ANA titer may be very low).

• #48 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In primary Raynaud phenomenon, an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels results in the vasoconstrictive response to cold temperatures and emotional stress. […] In secondary Raynaud phenomenon, the underlying disease is the factor that disrupts normal vessel reactivity to cold temperatures. Usually, the endothelial function of the digital and cutaneous vessels is compromised leading to eventual vasoconstriction with resulting tissue ischemia. For instance, fibrosis of the vascular system in systemic scleroderma leads to endothelial dysfunction followed by tissue ischemia.

• #49 Raynaud syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Raynaud_syndrome

  Raynaud’s disease, or primary Raynaud’s, is diagnosed if the symptoms are idiopathic, that is, if they occur by themselves and not in association with other diseases. […] Three main changes are seen in the mechanism of Raynaud’s phenomenon which are reduced blood flow, blood vessel constriction, and neurogenic, inflammatory, and immune responses. It is induced by mental stress and a cold atmosphere. In all cases, the primary cause is an underlying hyperactivation of the sympathetic nervous system. […] In the primary type, there is an increase in sensitivity due to the reasons mentioned above resulting in vasoconstriction. In the secondary type, normal activity of blood vessels is disrupted due to the same reasons mentioned above causing vasoconstriction which leads to ischemia and tissue death.

• #50 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The role of endothelin-1 in pathogenesis of primary RP has also been implicated in some studies, but the evidence is weaker in comparison with SSc. […] Calcitonin gene-related peptide (CGRP) is a neuropeptide and a potent vasodilator produced by peripheral sensory nerves. In RP (primary and secondary RP in SSc), especially the secondary forms in SSc, a reduction in the number of CGRP immunoreactive neurons in the skin was found.

• #51 Raynaud’s phenomenon — the clinical picture, treatment and diagnostics | Walecka | Acta Angiologica

  https://journals.viamedica.pl/acta_angiologica/article/view/AA.2017.0003/44433

  Raynauds disease primary Raynauds phenomenon […] Raynauds disease is a relatively rare phenomenon, affecting 510% of the population worldwide. The incidence may vary depending on the patients gender (1% of men, 20% of women) or climate. It is a vasomotor disorder of small vessels of acral parts of the body, where a sudden pallor is observed. This symptom is symmetrical, however, it may present with varying severity in different locations. The aberration of blood flow caused by the sudden vasospasm of small vessels is not severe enough to cause necrosis or other trophic lesions due to limited blood supply. As Raynauds disease is only a functional disorder, no structural changes of the vessel wall are present. Comparing with the secondary Raynauds syndrome, the vasospasm in Raynauds disease is relatively rare, less severe and patients usually lack anti-nuclear antibodies ANA (or the ANA titer may be very low).

• #52 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In primary Raynaud phenomenon, an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels results in the vasoconstrictive response to cold temperatures and emotional stress. […] In secondary Raynaud phenomenon, the underlying disease is the factor that disrupts normal vessel reactivity to cold temperatures. Usually, the endothelial function of the digital and cutaneous vessels is compromised leading to eventual vasoconstriction with resulting tissue ischemia. For instance, fibrosis of the vascular system in systemic scleroderma leads to endothelial dysfunction followed by tissue ischemia.

• #53 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  Raynauds phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. […] The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. […] In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. […] The complex pathogenesis of RP remains incompletely understood. […] Primary and secondary RP likely follow distinct pathogenetic pathways. […] In primary RP, vascular abnormalities are primarily functional, while secondary RP exhibits both structural and functional impairments. […] Endothelial dysfunction, a key factor in secondary RP, particularly SSc, disrupts the endotheliums normal function.

• #54 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  While primary RP is related to functional alterations alone, in RP secondary to SSc, structural alterations of the vascular wall are also found. […] Hyperactivity of the 2-adrenoceptor and alteration in the production of neuropeptides (e.g. calcitonin gene-related peptide), are some of the mechanisms involved in the vasospasm episodes induced by cold in primary and secondary RP. […] In RP, especially when secondary to SSc, endothelial lesion and activation cause an imbalance between the production of vasoconstrictors and vasodilatory mediators, with an increase in the production of endothelin-1 (powerful vasoconstrictor) and a decrease in the production of NO and prostacyclin (vasodilating agents). […] Besides the functional and contractile alterations, structural alterations are found in secondary RP, mainly in SSc. Proliferation and intimal fibrosis of the small arteries and arterioles result in decrease of vessel lumen; these alterations cause decrease of blood flow and lead to a state of chronic ischemia of the involved organs.

• #55

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  In Raynauds disease, the vascular abnormality is mostly functional while in secondary cases, the abnormality is both structural and functional leading to compromise in vascularity. […] Endothelial dysfunction- Disturbance of homeostasis of endothelial cells may cause vasoconstriction. […] A deficiency of nitric oxide (NO), a vasodilator may also be a contributory factor. […] In systemic sclerosis cases, fibrotic intimal proliferation and minimal proliferation of tunica media of vessels have been observed. […] Concurrent with intimal proliferation and because of anti-endothelial cell antibodies, there is endothelial cell damage as well. […] The tone of cutaneous vessels is adjusted by the transmitters released by sensory and autonomic nerves. In Raynauds case, vasoconstriction is mediated by neuropeptide dysregulation and 2-adrenoreceptors upregulation.

• #56 Pediatric Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1355650-overview

  The pathophysiology of Raynaud phenomenon is not completely understood; the vasospasm that occurs in the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts involves both central and peripheral mechanisms. […] The pathophysiology of secondary Raynaud phenomenon also involves structural changes to the vasculature that worsens the severity of the Raynaud phenomenon. […] Raynaud phenomenon can be thought of as an exaggerated normal response to cold and emotional stress. […] Primary Raynaud phenomenon rarely affects the nutritive flow, whereas secondary Raynaud phenomenon can cause digital artery vasospasm severe enough to block the nutritive flow, leading to tissue hypoxia and ischemia. […] Structural vascular defects in patients with secondary Raynaud phenomenon who have systemic sclerosis include endothelial cell apoptosis (due to repeated ischemia and antiendothelial cell antibodies), upregulation of adhesion molecules, formation of fibrous intimal lesions, intimal proliferation, capillary enlargement and atrophy, obliteration of vessel patency by perivascular fibrosis or thrombus formation, and defective vascular remodeling and arteriogenesis. […] Functional vascular defects include impaired endothelial-dependent vasodilation, decreased production of vasodilator substances (increased production of endothelial nitric oxide synthetase inhibitor), and increased production of vasoconstrictors such as endothelin-1 and angiotensin II in systemic sclerosis patients.

• #57 Raynaud’s Phenomenon – Life Extension

  https://www.lifeextension.com/protocols/heart-circulatory/raynauds-phenomenon?srsltid=AfmBOopCu2Ho1xjGBpE2n0061qg7BrVd4CLzDD3w8Y7b8ieykWzR2o82

  Various blood vessel abnormalities observed in secondary Raynauds phenomenon occur as a consequence of an underlying connective tissue disease, such as systemic sclerosis. These include enlarged, widened capillaries through which blood flow is sluggish. One of the most significant changes appears to be the increased thickness of the endothelium. Other contributors to vascular damage include the apoptosis, or programmed cell death, of endothelial cells; abnormal expression of transcription factors, which are proteins required for normal genetic processes; aberrant production of inflammatory cytokines; and irregularities in angiogenesis, which is the production and growth of blood vessels. […] One such vasoactive chemical that has received intense scrutiny in the context of Raynauds phenomenon is nitric oxide (NO). There are several forms of nitric oxide synthase (NOS), the enzyme that produces nitric oxide; in secondary Raynauds, some forms are overexpressed and others are underexpressed, complicating a clear understanding of nitric oxides role in the condition. Both increased and decreased nitric oxide production were reported in various studies, and the overall effect of NO in this condition was referred to as paradoxical, because it has positive as well as negative components. Nonetheless, studies show that applying topical nitroglycerin, a compound that increases nitric oxide generation, provokes vasodilation in both primary and secondary Raynauds phenomenon and may relieve symptoms.

• #58 Pediatric Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1355650-overview

  The pathophysiology of Raynaud phenomenon is not completely understood; the vasospasm that occurs in the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts involves both central and peripheral mechanisms. […] The pathophysiology of secondary Raynaud phenomenon also involves structural changes to the vasculature that worsens the severity of the Raynaud phenomenon. […] Raynaud phenomenon can be thought of as an exaggerated normal response to cold and emotional stress. […] Primary Raynaud phenomenon rarely affects the nutritive flow, whereas secondary Raynaud phenomenon can cause digital artery vasospasm severe enough to block the nutritive flow, leading to tissue hypoxia and ischemia. […] Structural vascular defects in patients with secondary Raynaud phenomenon who have systemic sclerosis include endothelial cell apoptosis (due to repeated ischemia and antiendothelial cell antibodies), upregulation of adhesion molecules, formation of fibrous intimal lesions, intimal proliferation, capillary enlargement and atrophy, obliteration of vessel patency by perivascular fibrosis or thrombus formation, and defective vascular remodeling and arteriogenesis. […] Functional vascular defects include impaired endothelial-dependent vasodilation, decreased production of vasodilator substances (increased production of endothelial nitric oxide synthetase inhibitor), and increased production of vasoconstrictors such as endothelin-1 and angiotensin II in systemic sclerosis patients.

• #59 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  In the microcirculation, capillary loss and dilatation are the most remarkable feature and lead to an important distortion of the capillary vascular architecture. […] The alterations in the microcirculation are also frequently associated with intravascular thrombus, which can cause a complete obstruction of the vessel lumen. […] It is suggested that in SSc, it’s suggested that the repeated episodes of reperfusion-ischemia cause an increase in free radicals activity (oxidative stress) and a persistent activation of the endothelial system. […] Finally, several intravascular abnormalities, such as platelet activation, increase of the fibrinolysis, leukocyte activation, and reduction of the deformation capacity of the red blood cells have been implicated as coadjuvant factors in the RP pathogenesis.

• #60 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  While primary RP is related to functional alterations alone, in RP secondary to SSc, structural alterations of the vascular wall are also found. […] Hyperactivity of the 2-adrenoceptor and alteration in the production of neuropeptides (e.g. calcitonin gene-related peptide), are some of the mechanisms involved in the vasospasm episodes induced by cold in primary and secondary RP. […] In RP, especially when secondary to SSc, endothelial lesion and activation cause an imbalance between the production of vasoconstrictors and vasodilatory mediators, with an increase in the production of endothelin-1 (powerful vasoconstrictor) and a decrease in the production of NO and prostacyclin (vasodilating agents). […] Besides the functional and contractile alterations, structural alterations are found in secondary RP, mainly in SSc. Proliferation and intimal fibrosis of the small arteries and arterioles result in decrease of vessel lumen; these alterations cause decrease of blood flow and lead to a state of chronic ischemia of the involved organs.

• #61 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The vasospasm in primary RP is reversible, while the secondary Raynauds phenomenon in systemic sclerosis is associated with endothelial injury and subsequent structural abnormalities that lead to tissue damage. […] Adrenergic alpha-2 receptors that are more important than alpha-1 receptors in the control of vasoconstriction of digital arteries are suggested to be abnormal in RP. The receptor subtype alpha-2c is found to predominate in the vascular smooth muscle cells of distal cutaneous vessels. […] The endothelium controls blood vessel tone via production of vasodilators (nitric oxide (NO), prostacyclin) and vasoconstrictors (endothelin-1, angiotensin). Endothelial damage in secondary RP in SSc leads to disbalance between vasodilators and vasoconstrictors. […] In SSc, endothelial injury represents a key pathogenic step that mediates the processes of inflammation, thrombus formation, and fibrosis.

• #62 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  In the microcirculation, capillary loss and dilatation are the most remarkable feature and lead to an important distortion of the capillary vascular architecture. […] The alterations in the microcirculation are also frequently associated with intravascular thrombus, which can cause a complete obstruction of the vessel lumen. […] It is suggested that in SSc, it’s suggested that the repeated episodes of reperfusion-ischemia cause an increase in free radicals activity (oxidative stress) and a persistent activation of the endothelial system. […] Finally, several intravascular abnormalities, such as platelet activation, increase of the fibrinolysis, leukocyte activation, and reduction of the deformation capacity of the red blood cells have been implicated as coadjuvant factors in the RP pathogenesis.

• #63 Raynaud’s Phenomenon – Life Extension

  https://www.lifeextension.com/protocols/heart-circulatory/raynauds-phenomenon?srsltid=AfmBOopCu2Ho1xjGBpE2n0061qg7BrVd4CLzDD3w8Y7b8ieykWzR2o82

  Oxidative stress is implicated not only in the pathogenesis of Raynauds phenomenon, but can be a significant consequence of the ischemia-reperfusion characteristic of both the primary and secondary forms of this disease as well. Lack of blood flow (ischemia), and its subsequent return (reperfusion), generates free radicals, which can damage the delicate interior lining of the blood vessels, called the endothelium, in the affected tissues; in severe cases this may lead to ulcers and tissue death. Therefore, antioxidants, which neutralize free radicals, have received significant attention among researchers studying Raynauds phenomenon. […] A key feature of secondary Raynauds phenomenon is a disruption of the vasodilation/vasoconstriction equilibrium, resulting in decreased vasodilation and increased vasoconstriction. This appears to be a consequence of decreased production of chemicals that dilate blood vessels, combined with the increased production of chemicals that constrict them.

• #64 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  In the microcirculation, capillary loss and dilatation are the most remarkable feature and lead to an important distortion of the capillary vascular architecture. […] The alterations in the microcirculation are also frequently associated with intravascular thrombus, which can cause a complete obstruction of the vessel lumen. […] It is suggested that in SSc, it’s suggested that the repeated episodes of reperfusion-ischemia cause an increase in free radicals activity (oxidative stress) and a persistent activation of the endothelial system. […] Finally, several intravascular abnormalities, such as platelet activation, increase of the fibrinolysis, leukocyte activation, and reduction of the deformation capacity of the red blood cells have been implicated as coadjuvant factors in the RP pathogenesis.

• #65

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Stress-induced Raynauds phenomenon suggests the involvement of our nervous system in its pathophysiology. […] In Raynauds patients, calcitonin gene-related peptide (vasodilatory) release from neurons supplying vessels is diminished. […] The ability of sympathetic nerves to get stimulated to cause vasoconstriction on the cooling of the body is augmented in Raynauds patients. […] Various intravascular circulatory factors might cause/exacerbate Raynauds phenomenon, especially in secondary cases. […] Platelet activation and aggregation has been noticed in Raynauds cases. […] Recurrent episodes of vasospasm lead to reperfusion injury of endothelial cells by augmenting the production of reactive oxygen species. […] Other factors like estrogen and genetics might play a role.

• #66 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  In the microcirculation, capillary loss and dilatation are the most remarkable feature and lead to an important distortion of the capillary vascular architecture. […] The alterations in the microcirculation are also frequently associated with intravascular thrombus, which can cause a complete obstruction of the vessel lumen. […] It is suggested that in SSc, it’s suggested that the repeated episodes of reperfusion-ischemia cause an increase in free radicals activity (oxidative stress) and a persistent activation of the endothelial system. […] Finally, several intravascular abnormalities, such as platelet activation, increase of the fibrinolysis, leukocyte activation, and reduction of the deformation capacity of the red blood cells have been implicated as coadjuvant factors in the RP pathogenesis.

• #67 Raynaud’s Phenomenon – Life Extension

  https://www.lifeextension.com/protocols/heart-circulatory/raynauds-phenomenon?srsltid=AfmBOopCu2Ho1xjGBpE2n0061qg7BrVd4CLzDD3w8Y7b8ieykWzR2o82

  Oxidative stress is implicated not only in the pathogenesis of Raynauds phenomenon, but can be a significant consequence of the ischemia-reperfusion characteristic of both the primary and secondary forms of this disease as well. Lack of blood flow (ischemia), and its subsequent return (reperfusion), generates free radicals, which can damage the delicate interior lining of the blood vessels, called the endothelium, in the affected tissues; in severe cases this may lead to ulcers and tissue death. Therefore, antioxidants, which neutralize free radicals, have received significant attention among researchers studying Raynauds phenomenon. […] A key feature of secondary Raynauds phenomenon is a disruption of the vasodilation/vasoconstriction equilibrium, resulting in decreased vasodilation and increased vasoconstriction. This appears to be a consequence of decreased production of chemicals that dilate blood vessels, combined with the increased production of chemicals that constrict them.

• #68 Researchers find genetic cause of Raynaud’s phenomenon – Queen Mary University of London

  https://www.qmul.ac.uk/media/news/2023/smd/researchers-find-genetic-cause-of-raynauds-phenomenon-.html

  Researchers at Queen Mary University of Londons Precision Healthcare Research Institute (PHURI) and the Berlin Institute of Health (BIH) at Charit Universittsmedizin Berlin have identified the genetic causes of Raynauds phenomenon. […] Raynauds phenomenon (RP) is a heritable condition that affects blood circulation. Its a vasospastic condition, which means that small blood vessels near the surface of the skin have spasms that can limit blood flow. […] A better understanding of the underlying genetic mechanisms that cause RD is needed to develop safe and effective treatments. […] The researchers discovered variation in two genes that predisposed participants to Raynaud’s phenomenon: One was the alpha-2A-adrenergic receptor for adrenaline, ADRA2A, a classic stress receptor that causes the small blood vessels to contract.

• #69 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Raynauds phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. […] We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p9.61027) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.121.22, p4.81013) as candidate causal genes through integration of gene expression in disease relevant tissues. […] Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of 2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms. […] We highlight two independent disease mechanisms supported by those loci that challenge and advance our current understanding of primary RP, with ADRA2A highlighting the role of 2A-adrenoreceptors and IRX1 as a putative regulator of vasodilation by altering prostaglandin and/or bradykinin responsiveness.

• #70 Researchers find genetic cause of Raynaud’s phenomenon – Queen Mary University of London

  https://www.qmul.ac.uk/media/news/2023/smd/researchers-find-genetic-cause-of-raynauds-phenomenon-.html

  Researchers at Queen Mary University of Londons Precision Healthcare Research Institute (PHURI) and the Berlin Institute of Health (BIH) at Charit Universittsmedizin Berlin have identified the genetic causes of Raynauds phenomenon. […] Raynauds phenomenon (RP) is a heritable condition that affects blood circulation. Its a vasospastic condition, which means that small blood vessels near the surface of the skin have spasms that can limit blood flow. […] A better understanding of the underlying genetic mechanisms that cause RD is needed to develop safe and effective treatments. […] The researchers discovered variation in two genes that predisposed participants to Raynaud’s phenomenon: One was the alpha-2A-adrenergic receptor for adrenaline, ADRA2A, a classic stress receptor that causes the small blood vessels to contract.

• #71 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Raynauds phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. […] We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p9.61027) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.121.22, p4.81013) as candidate causal genes through integration of gene expression in disease relevant tissues. […] Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of 2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms. […] We highlight two independent disease mechanisms supported by those loci that challenge and advance our current understanding of primary RP, with ADRA2A highlighting the role of 2A-adrenoreceptors and IRX1 as a putative regulator of vasodilation by altering prostaglandin and/or bradykinin responsiveness.

• #72 Researchers find genetic cause of Raynaud’s phenomenon – Queen Mary University of London

  https://www.qmul.ac.uk/media/news/2023/smd/researchers-find-genetic-cause-of-raynauds-phenomenon-.html

  In Raynaud’s patients, this receptor seemed to be particularly active, which could explain the vasospasms, especially in combination with the second gene that we found: This gene is the transcription factor IRX1, which may regulate the ability of blood vessels to dilate. […] If its production is increased, it may activate genes that prevent constricted vessels from relaxing as they would normally do. Together with the overactive adrenaline receptor, this may then lead to the vessels not suppling enough blood for a longer period of time, which leads to the observed white fingers and toes. […] The researchers findings help to understand, for the first time, why the small vessels react so strongly in patients, even apparently without external stimuli, such as exposure to cold. […] Approved drugs that more or less specifically inhibit the function of ADRA2A, such as the antidepressant mirtazapine, already exist, and our results suggest that these may present alternative treatment options for patients suffering from the symptoms of Raynauds.

• #73 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Raynauds phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. […] We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p9.61027) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.121.22, p4.81013) as candidate causal genes through integration of gene expression in disease relevant tissues. […] Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of 2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms. […] We highlight two independent disease mechanisms supported by those loci that challenge and advance our current understanding of primary RP, with ADRA2A highlighting the role of 2A-adrenoreceptors and IRX1 as a putative regulator of vasodilation by altering prostaglandin and/or bradykinin responsiveness.

• #74 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Our finding may imply that overstimulation or increased expression of 2A-adrenergic receptors contributes to the vasospastic effects characteristic of RP and its symptoms, also in line with RP being an adverse effect of 2-adrenergic agonists such as clonidine. […] The RP-increasing effect-allele of rs11748327 was associated with higher expression of IRX1 in skeletal muscle (beta=0.57, p=1.11022) and tibial artery (beta=0.42, p=5.71011), suggesting that higher gene expression confers a higher risk for RP. […] We lastly observed no strong evidence for a shared genetic architecture with suspected cardiovascular comorbidities for primary RP but did observe a novel detrimental effect of low fasting plasma glucose that might help to guide primary RP management.

• #75 Researchers find genetic cause of Raynaud’s phenomenon – Queen Mary University of London

  https://www.qmul.ac.uk/media/news/2023/smd/researchers-find-genetic-cause-of-raynauds-phenomenon-.html

  In Raynaud’s patients, this receptor seemed to be particularly active, which could explain the vasospasms, especially in combination with the second gene that we found: This gene is the transcription factor IRX1, which may regulate the ability of blood vessels to dilate. […] If its production is increased, it may activate genes that prevent constricted vessels from relaxing as they would normally do. Together with the overactive adrenaline receptor, this may then lead to the vessels not suppling enough blood for a longer period of time, which leads to the observed white fingers and toes. […] The researchers findings help to understand, for the first time, why the small vessels react so strongly in patients, even apparently without external stimuli, such as exposure to cold. […] Approved drugs that more or less specifically inhibit the function of ADRA2A, such as the antidepressant mirtazapine, already exist, and our results suggest that these may present alternative treatment options for patients suffering from the symptoms of Raynauds.

• #76

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Raynauds phenomenon manifests as episodic vasospasm leading to acral vascular compromise following emotional stress or exposure to a cold environment. […] The distinction between Raynauds disease and secondary Raynauds phenomenon is of utmost importance because of differences in pathophysiology and hence natural course, prognosis, complications, associations, and treatment. […] Pathogenesis underlying Raynauds phenomenon had not yet been properly elucidated. Initially, Raynaud hypothesized that these vasospastic episodes develop secondary to irritability of the spinal cord affecting vascular innervation. Around 70 years later, Lewis and Pickering suggested that local effects cause vascular spasms, not CNS abnormalities. […] Multiple factors including mediators released by blood cells, blood vessels, hormones, and probably neuronal factors control blood vessel reactivity. Herrick divided pathophysiological mechanisms into three major parts, abnormalities in vessels, abnormalities in the nervous system, and abnormalities within the vessels.

• #77 Pathogenesis of Raynaud’s phenomenon – PubMed

  https://pubmed.ncbi.nlm.nih.gov/15741200/

  The pathogenesis of Raynaud’s phenomenon is not fully understood. However, the last 20 yr have witnessed enormous increases in our understanding of different mechanisms which, singly or in combination, may contribute. A key point is that Raynaud’s phenomenon can be either primary (idiopathic) or secondary to a number of underlying conditions, and that the pathogenesis and pathophysiology vary between these conditions. […] In this review, I shall discuss the main mechanisms thought to be important in pathophysiology under the three broad headings of 'vascular’, 'neural’ and 'intravascular’. While these are false distinctions because all interrelate, they facilitate discussion of the key elements: the blood vessel wall (particularly the endothelium), the neural control of vascular tone, and the many circulating factors which can impair blood flow and/or cause endothelial injury. Vascular abnormalities include those of both structure and function. Neural abnormalities include deficiency of the vasodilator calcitonin gene-related peptide (released from sensory afferents), alpha(2)-adrenoreceptor activation (possibly with up-regulation of the normally 'silent’ alpha(2C)-adrenoreceptor) and a central nervous system component. Intravascular abnormalities include platelet activation, impaired fibrinolysis, increased viscosity and probably oxidant stress. As our understanding of the pathophysiology of Raynaud’s phenomenon increases, so do our possibilities for identifying effective treatments.

• #78 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In primary Raynaud phenomenon, an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels results in the vasoconstrictive response to cold temperatures and emotional stress. […] In secondary Raynaud phenomenon, the underlying disease is the factor that disrupts normal vessel reactivity to cold temperatures. Usually, the endothelial function of the digital and cutaneous vessels is compromised leading to eventual vasoconstriction with resulting tissue ischemia. For instance, fibrosis of the vascular system in systemic scleroderma leads to endothelial dysfunction followed by tissue ischemia.

• #79 Raynaud’s Phenomenon – Life Extension

  https://www.lifeextension.com/protocols/heart-circulatory/raynauds-phenomenon?srsltid=AfmBOopCu2Ho1xjGBpE2n0061qg7BrVd4CLzDD3w8Y7b8ieykWzR2o82

  Raynauds phenomenon is a disorder in which blood vessels overreact to cold temperature or stress. Generally, blood vessels in fingers or toes are most affected. The blood vessels constrict, causing reduced blood flow to the affected extremity. Primary Raynauds phenomenon has no identified underlying cause and is generally not permanently damaging. Secondary Raynauds phenomenon, however, is related to an underlying cause and may be more damaging to the affected tissue. […] Although the causes(s) of primary Raynauds phenomenon are not entirely understood, a significant underlying feature appears to be an abnormal response of alpha-2 adrenergic receptors, which are proteins on cell surfaces that bind to hormones like norepinephrine and epinephrine and help control the stress response, regulate blood pressure, and control heart rate. Alpha-2 adrenergic receptors are particularly abundant within the blood vessels in the fingers, and their abnormal response can cause vasoconstriction. This process occurs in response to cold or emotional stress, and may be driven in part by free radicals, which cause oxidative stress.

• #80 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The vasospasm in primary RP is reversible, while the secondary Raynauds phenomenon in systemic sclerosis is associated with endothelial injury and subsequent structural abnormalities that lead to tissue damage. […] Adrenergic alpha-2 receptors that are more important than alpha-1 receptors in the control of vasoconstriction of digital arteries are suggested to be abnormal in RP. The receptor subtype alpha-2c is found to predominate in the vascular smooth muscle cells of distal cutaneous vessels. […] The endothelium controls blood vessel tone via production of vasodilators (nitric oxide (NO), prostacyclin) and vasoconstrictors (endothelin-1, angiotensin). Endothelial damage in secondary RP in SSc leads to disbalance between vasodilators and vasoconstrictors. […] In SSc, endothelial injury represents a key pathogenic step that mediates the processes of inflammation, thrombus formation, and fibrosis.

• #81 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  While primary RP is related to functional alterations alone, in RP secondary to SSc, structural alterations of the vascular wall are also found. […] Hyperactivity of the 2-adrenoceptor and alteration in the production of neuropeptides (e.g. calcitonin gene-related peptide), are some of the mechanisms involved in the vasospasm episodes induced by cold in primary and secondary RP. […] In RP, especially when secondary to SSc, endothelial lesion and activation cause an imbalance between the production of vasoconstrictors and vasodilatory mediators, with an increase in the production of endothelin-1 (powerful vasoconstrictor) and a decrease in the production of NO and prostacyclin (vasodilating agents). […] Besides the functional and contractile alterations, structural alterations are found in secondary RP, mainly in SSc. Proliferation and intimal fibrosis of the small arteries and arterioles result in decrease of vessel lumen; these alterations cause decrease of blood flow and lead to a state of chronic ischemia of the involved organs.

• #82

  https://journals.lww.com/idoj/fulltext/2023/14020/raynaud_s_phenomenon__a_brush_up_.15.aspx

  Stress-induced Raynauds phenomenon suggests the involvement of our nervous system in its pathophysiology. […] In Raynauds patients, calcitonin gene-related peptide (vasodilatory) release from neurons supplying vessels is diminished. […] The ability of sympathetic nerves to get stimulated to cause vasoconstriction on the cooling of the body is augmented in Raynauds patients. […] Various intravascular circulatory factors might cause/exacerbate Raynauds phenomenon, especially in secondary cases. […] Platelet activation and aggregation has been noticed in Raynauds cases. […] Recurrent episodes of vasospasm lead to reperfusion injury of endothelial cells by augmenting the production of reactive oxygen species. […] Other factors like estrogen and genetics might play a role.

• #83 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?pn=mostcited&uid=1349&vmd=Full

  The neural pathogenic mechanism may originate from cold-induced increased sympathetic tone or, in some cases, peripheral nerve compression. […] Regarding intravascular factors, both primary and secondary RP involve platelet activation and the subsequent release of vasoactive substances like thromboxane and serotonin, which further promote platelet aggregation. […] Impaired erythrocyte flexibility and increased blood viscosity in RP contribute to the rationale for using rheologic drugs like pentoxifylline to improve blood flow. […] A summary of the factors involved in RP pathogenesis is presented in Fig. 1.

• #84 Raynaud’s Phenomenon – Life Extension

  https://www.lifeextension.com/protocols/heart-circulatory/raynauds-phenomenon?srsltid=AfmBOopCu2Ho1xjGBpE2n0061qg7BrVd4CLzDD3w8Y7b8ieykWzR2o82

  Oxidative stress is implicated not only in the pathogenesis of Raynauds phenomenon, but can be a significant consequence of the ischemia-reperfusion characteristic of both the primary and secondary forms of this disease as well. Lack of blood flow (ischemia), and its subsequent return (reperfusion), generates free radicals, which can damage the delicate interior lining of the blood vessels, called the endothelium, in the affected tissues; in severe cases this may lead to ulcers and tissue death. Therefore, antioxidants, which neutralize free radicals, have received significant attention among researchers studying Raynauds phenomenon. […] A key feature of secondary Raynauds phenomenon is a disruption of the vasodilation/vasoconstriction equilibrium, resulting in decreased vasodilation and increased vasoconstriction. This appears to be a consequence of decreased production of chemicals that dilate blood vessels, combined with the increased production of chemicals that constrict them.

• #85 Researchers find genetic cause of Raynaud’s phenomenon – Queen Mary University of London

  https://www.qmul.ac.uk/media/news/2023/smd/researchers-find-genetic-cause-of-raynauds-phenomenon-.html

  Researchers at Queen Mary University of Londons Precision Healthcare Research Institute (PHURI) and the Berlin Institute of Health (BIH) at Charit Universittsmedizin Berlin have identified the genetic causes of Raynauds phenomenon. […] Raynauds phenomenon (RP) is a heritable condition that affects blood circulation. Its a vasospastic condition, which means that small blood vessels near the surface of the skin have spasms that can limit blood flow. […] A better understanding of the underlying genetic mechanisms that cause RD is needed to develop safe and effective treatments. […] The researchers discovered variation in two genes that predisposed participants to Raynaud’s phenomenon: One was the alpha-2A-adrenergic receptor for adrenaline, ADRA2A, a classic stress receptor that causes the small blood vessels to contract.

• #86 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Raynauds-Syndrome.aspx

  Raynaud’s syndrome, also called Raynaud’s phenomenon, is an exaggerated response to cold or stress induced vasospasm of cutaneous blood vessels. […] The vasospasm or constriction of blood vessels protects the body from excessive heat loss, and hence can be observed as a compensating mechanism. This protective mechanism is mediated by the release of norepinephrine from the sympathetic nervous system. […] The secondary form is more common in patients suffering from connective tissue disease, and the condition worsens in the presence of external strain (physical/chemical). The secondary form can progress to more severe forms, such as digital necrosis and ulceration, which leads to disability. Hence, a detailed investigation for prompt diagnosis of the underlying disease is necessary. […] Research focusing on elucidating the exact mechanisms regulating the various vasoconstriction and vasodilation pathways is vital. This can ultimately deliver promising agents for the treatment of Raynauds syndrome, especially the secondary form of the disease.

• #87 Raynaud’s phenomenon — the clinical picture, treatment and diagnostics | Walecka | Acta Angiologica

  https://journals.viamedica.pl/acta_angiologica/article/view/AA.2017.0003/44433

  Pathogenesis of Raynauds phenomenon […] Pathophysiology of the whole process is sophisticated and not well established. However, it is indubitable that the RP results from the imbalance of intravascular chemical factors (a predominance of vasoconstrictive factors) and anatomic issues (affecting only small vessels). Decreased production of nitric oxide (NO) with increased levels of endothelin-1 profoundly limits the vasodilatation, triggering excessive vasoconstriction. Due to the elevated levels of profibrotic factors such as endothelin-1 and angiotensin, the innermost layer of the vessel walls (tunica intima) becomes thicker, which additionally limits vasomotor activity. It has been documented, that the frequency of sudden vasospasms is higher in the pre-ovulation period and during estrogen therapy, which proves the distinct influence of estrogens on the pathogenesis of this process. […]

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