Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A vascular mechanistic approach to understanding Raynaud phenomenon

Key Points

  • During cold exposure, human bodies attempt to maintain core temperature by reducing heat loss via cutaneous vasoconstriction and by increasing heat production via shivering and nonshivering thermogenesis

  • In selected skin areas, nutritional capillaries are bypassed by arteriovenous anastomoses; these thermoregulatory structures are predominantly closed during heat conservation and fully dilated during heat elimination

  • Cold exposure activates and amplifies sympathetic nervous system signalling, triggering cutaneous vasoconstriction and thermogenesis: sympathetic vasoconstriction selectively restricts blood flow through arteriovenous anastomoses while protecting nutritional capillary blood flow

  • In Raynaud phenomenon, the already heightened sympathetic vasoconstriction in areas rich in arteriovenous anastomoses is further amplified in intensity and scope, with expansion into the adjoining nutritional system

  • Cold-induced vasospasm and interruption of capillary blood flow is mediated by sympathetic vasoconstriction, and modulation by endothelial vasodilatation perhaps contributes to differences between primary and secondary forms of Raynaud phenomenon

  • Despite the exuberant increase in cold-induced vasoconstriction in Raynaud phenomenon, reflecting upregulation of heat-conservation mechanisms, surprisingly little is known about thermogenesis in this disorder

Abstract

During exposure to cold, our bodies attempt to maintain normal core temperature by restricting heat loss through cutaneous vasoconstriction, and by increasing heat production through shivering and nonshivering thermogenesis. In selected areas of human skin (including on the fingers and toes), the vascular system has specialized structural and functional features that enable it to contribute to thermoregulation. These features include arteriovenous anastomoses, which directly connect the arterial and venous systems and bypass the nutritional capillaries supplying blood to the skin tissue. Of note, Raynaud phenomenon predominantly affects the arterial territories supplying these specialized areas of skin. Indeed, Raynaud phenomenon can be considered a disorder of vascular thermoregulatory control. This Review presents an understanding of Raynaud phenomenon in the context of vascular and thermoregulatory control mechanisms, including the role of unique thermosensitive vascular structural and functional specialization, and describes the potential role of thermogenesis in this disorder. This new approach provides remarkable insight into the disease process and builds a framework to critically appraise the existing knowledge base. This paradigm also explains the deficiencies in some current therapeutic approaches, and highlights new areas of potential relevance to the pathogenesis and treatment of Raynaud phenomenon that should be expanded and explored.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure of the human cutaneous microvascular system.
Figure 2: Arteriovenous anastomoses in the cutaneous circulation.
Figure 3: Simultaneous measurements of blood flow velocity in the third fingers of the left (blue circles) and right (red circles) hands of an individual unaffected by Raynaud phenomenon.
Figure 4: Cold-induced digital vasoconstriction in Raynaud phenomenon.

Similar content being viewed by others

References

  1. Burton, A. C. The range and variability of the blood flow in the human fingers and the vasomotor regulation by body temperature. Am. J. Physiol. 127, 437–453 (1939).

    Article  Google Scholar 

  2. Charkoudian, N. Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J. Appl. Physiol. (1985) 109, 1221–1228 (2010).

    Article  Google Scholar 

  3. Herrick, A. L. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat. Rev. Rheumatol. 8, 469–479 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. LeRoy, E. C. & Medsger, T. A. Jr. Raynaud's phenomenon: a proposal for classification. Clin. Exp. Rheumatol. 10, 485–488 (1992).

    CAS  PubMed  Google Scholar 

  5. Maverakis, E. et al. International consensus criteria for the diagnosis of Raynaud's phenomenon. J. Autoimmun. 48–49, 60–65 (2014).

    Article  PubMed  Google Scholar 

  6. Taylor, G. I. in Grabb and Smith's Plastic Surgery (eds. Thorne, C. H. et al.) 33–41 (Lippincott, Williams & Wilkins, 2007).

    Google Scholar 

  7. Braverman, I. M. The cutaneous microcirculation. J. Investig. Dermatol. Symp. Proc. 5, 3–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Sangiorgi, S. et al. Microvascularization of the human digit as studied by corrosion casting. J. Anat. 204, 123–131 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Thoresen, M. & Walloe, L. Skin blood flow in humans as a function of environmental temperature measured by ultrasound. Acta Physiol. Scand. 109, 333–341 (1980).

    Article  CAS  PubMed  Google Scholar 

  10. Lossius, K., Eriksen, M. & Walloe, L. Fluctuations in blood flow to acral skin in humans: connection with heart rate and blood pressure variability. J. Physiol. 460, 641–655 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Manelli, A. et al. Plexiform vascular structures in the human digital dermal layer: a SEM corrosion casting morphological study. Eur. J. Morphol. 42, 173–177 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Bergersen, T. K., Eriksen, M. & Walloe, L. Local constriction of arteriovenous anastomoses in the cooled finger. Am. J. Physiol. 273, R880–R886 (1997).

    CAS  PubMed  Google Scholar 

  13. Bergersen, T. K., Hisdal, J. & Walloe, L. Perfusion of the human finger during cold-induced vasodilatation. Am. J. Physiol. 276, R731–R737 (1999).

    CAS  PubMed  Google Scholar 

  14. Bini, G., Hagbarth, K. E., Hynninen, P. & Wallin, B. G. Regional similarities and differences in thermoregulatory vaso- and sudomotor tone. J. Physiol. 306, 553–565 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kellogg, D. L. Jr et al. Cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission. Circ. Res. 77, 1222–1228 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Nakamura, K. Central circuitries for body temperature regulation and fever. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1207–R1228 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Morrison, S. F. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: central neural pathways for thermoregulatory cold defence. J. Appl. Physiol. (1985) 110, 1137–1149 (2011).

    Article  CAS  Google Scholar 

  18. Flavahan, N. A., Lindblad, L. E., Verbeuren, T. J., Shepherd, J. T. & Vanhoutte, P. M. Cooling and α1- and α2-adrenergic responses in cutaneous veins: role of receptor reserve. Am. J. Physiol. 249, H950–H955 (1985).

    CAS  PubMed  Google Scholar 

  19. Honda, M., Suzuki, M., Nakayama, K. & Ishikawa, T. Role of α2C-adrenoceptors in the reduction of skin blood flow induced by local cooling in mice. Br. J. Pharmacol. 152, 91–100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sawasaki, N., Iwase, S. & Mano, T. Effect of skin sympathetic response to local or systemic cold exposure on thermoregulatory functions in humans. Autonom. Neurosci. 87, 274–281 (2001).

    Article  CAS  Google Scholar 

  21. Ootsuka, Y. & McAllen, R. M. Comparison between two rat sympathetic pathways activated in cold defence. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R589–R595 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Bini, G., Hagbarth, K. E., Hynninen, P. & Wallin, B. G. Thermoregulatory and rhythm-generating mechanisms governing the sudomotor and vasoconstrictor outflow in human cutaneous nerves. J. Physiol. 306, 537–552 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Coffman, J. D. Total and nutritional blood flow in the finger. Clin. Sci. 42, 243–250 (1972).

    Article  CAS  PubMed  Google Scholar 

  24. Hertzman, A. B. Vasomotor regulation of cutaneous circulation. Physiol. Rev. 39, 280–306 (1959).

    Article  CAS  PubMed  Google Scholar 

  25. McCook, R. D., Wurster, R. D. & Randall, W. C. Sudomotor and vasomotor responses to changing environmental temperature. J. Appl. Physiol. 20, 371–378 (1965).

    Article  CAS  PubMed  Google Scholar 

  26. Montgomery, L. D. & Williams, B. A. Variation of forearm, hand, and finger blood flow indices with ambient temperature. Aviat. Space Environ. Med. 48, 231–235 (1977).

    CAS  PubMed  Google Scholar 

  27. Coffman, J. D. & Cohen, A. S. Total and capillary fingertip blood flow in Raynaud's phenomenon. N. Engl. J. Med. 285, 259–263 (1971).

    Article  CAS  PubMed  Google Scholar 

  28. Saad, A. R. et al. Influence of isometric exercise on blood flow and sweating in glabrous and nonglabrous human skin. J. Appl. Physiol. (1985) 91, 2487–2492 (2001).

    Article  CAS  Google Scholar 

  29. Richardson, D., Schmitz, M. & Borchers, N. Relative effects of static muscle contraction on digital artery and nailfold capillary blood flow velocities. Microvasc. Res. 31, 157–169 (1986).

    Article  CAS  PubMed  Google Scholar 

  30. Haak, E. et al. The impact of contralateral cooling on skin capillary blood cell velocity in patients with diabetes mellitus. J. Vasc. Res. 35, 245–249 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Halperin, J. L., Cohen, R. A. & Coffman, J. D. Digital vasodilatation during mental stress in patients with Raynaud's disease. Cardiovasc. Res. 17, 671–677 (1983).

    Article  CAS  PubMed  Google Scholar 

  32. Kristensen, J. K., Engelhart, M. & Nielsen, T. Laser-Doppler measurement of digital blood flow regulation in normals and in patients with Raynaud's phenomenon. Acta Derm. Venereol. 63, 43–47 (1983).

    CAS  PubMed  Google Scholar 

  33. Engelhart, M. & Kristensen, J. K. Raynaud's phenomenon: blood supply to fingers during indirect cooling, evaluated by laser Doppler flowmetry. Clin. Physiol. 6, 481–488 (1986).

    Article  CAS  PubMed  Google Scholar 

  34. Smyth, A. E., Bell, A. L., Bruce, I. N., McGrann, S. & Allen, J. A. Digital vascular responses and serum endothelin-1 concentrations in primary and secondary Raynaud's phenomenon. Ann. Rheum. Dis. 59, 870–874 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cooke, J. P. et al. Role of digital artery adrenoceptors in Raynaud's disease. Vasc. Med. 2, 1–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Greenstein, D., Gupta, N. K., Martin, P., Walker, D. R. & Kester, R. C. Impaired thermoregulation in Raynaud's phenomenon. Angiology 46, 603–611 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Terregino, C. A. & Seibold, J. R. Influence of the menstrual cycle on Raynaud's phenomenon and on cold tolerance in normal women. Angiology 36, 88–95 (1985).

    Article  CAS  PubMed  Google Scholar 

  38. LeRoy, E. C., Downey, J. A. & Cannon, P. J. Skin capillary blood flow in scleroderma. J. Clin. Invest. 50, 930–939 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maricq, H. R., Downey, J. A. & LeRoy, E. C. Standstill of nailfold capillary blood flow during cooling in scleroderma and Raynaud's syndrome. Blood Vessels 13, 338–349 (1976).

    CAS  PubMed  Google Scholar 

  40. Recio, P. et al. Noradrenergic vasoconstriction of pig prostatic small arteries. Naunyn Schmiedebergs Arch. Pharmacol. 376, 397–406 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Flavahan, N. A. Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating α2-adrenoceptors. J. Pharmacol. Exp. Ther. 313, 432–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Flavahan, N. A. The role of α2-adrenoceptors as cutaneous thermosensors. News Physiol. Sci. 6, 251–255 (1991).

    CAS  Google Scholar 

  43. Flavahan, N. A. & Vanhoutte, P. M. Effect of cooling on α-1 and α-2 adrenergic responses in canine saphenous and femoral veins. J. Pharmacol. Exp. Ther. 238, 139–147 (1986).

    CAS  PubMed  Google Scholar 

  44. Chotani, M. A. et al. Regulation of α2-adrenoceptors in human vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 286, H59–H67 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Flavahan, N. A., Cooke, J. P., Shepherd, J. T. & Vanhoutte, P. M. Human postjunctional α-1 and α-2 adrenoceptors: differential distribution in arteries of the limbs. J. Pharmacol. Exp. Ther. 241, 361–365 (1987).

    CAS  PubMed  Google Scholar 

  46. Chotani, M. A. & Flavahan, N. A. Intracellular α2C-adrenoceptors: storage depot, stunted development or signalling domain? Biochim. Biophys. Acta 1813, 1495–1503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Flavahan, N. A., Rimele, T. J., Cooke, J. P. & Vanhoutte, P. M. Characterization of postjunctional α-1 and α-2 adrenoceptors activated by exogenous or nerve-released noradrenaline in the canine saphenous vein. J. Pharmacol. Exp. Ther. 230, 699–705 (1984).

    CAS  PubMed  Google Scholar 

  48. Coffman, J. D. & Cohen, R. A. Role of α-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits. Eur. J. Clin. Invest. 18, 309–313 (1988).

    Article  CAS  PubMed  Google Scholar 

  49. Coffman, J. D. & Cohen, R. A. α2-adrenergic and 5-HT2 receptor hypersensitivity in Raynaud's phenomenon. J. Vasc. Med. Biol. 2, 100–106 (1990).

    Google Scholar 

  50. Fagius, J. & Blumberg, H. Sympathetic outflow to the hand in patients with Raynaud's phenomenon. Cardiovasc. Res. 19, 249–253 (1985).

    Article  CAS  PubMed  Google Scholar 

  51. Freedman, R. R., Sabharal, S. C., Desai, N., Wenig, P. & Mayes, M. Increased α-adrenergic responsiveness in idiopathic Raynaud's disease. Arthritis Rheum. 32, 61–65 (1989).

    Article  CAS  PubMed  Google Scholar 

  52. Freedman, R. R., Moten, M., Migaly, P. & Mayes, M. Cold-induced potentiation of α 2-adrenergic vasoconstriction in primary Raynaud's disease. Arthritis Rheum. 36, 685–690 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Flavahan, N. A. et al. Increased α2-adrenergic constriction of isolated arterioles in diffuse scleroderma. Arthritis Rheum. 43, 1886–1890 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Carter, S. A., Dean, E. & Kroeger, E. A. Apparent finger systolic pressures during cooling in patients with Raynaud's syndrome. Circulation 77, 988–996 (1988).

    Article  CAS  PubMed  Google Scholar 

  55. Jamieson, G. G., Ludbrook, J. & Wilson, A. Cold hypersenstivity in Raynaud's phenomenon. Circulation 44, 254–264 (1971).

    Article  CAS  PubMed  Google Scholar 

  56. Bollinger, A. & Schlumpf, M. Finger blood flow in healthy subjects of different age and sex and in patients with primary Raynaud's disease. Acta Chir. Scand. Suppl. 465, 42–47 (1976).

    CAS  PubMed  Google Scholar 

  57. Nuzzaci, G. et al. Arteriovenous anastomoses' function and Raynaud's phenomenon. Angiology 39, 812–818 (1988).

    Article  CAS  PubMed  Google Scholar 

  58. Singh, S., de Trafford, J. C., Baskerville, P. A. & Roberts, V. C. Digital artery calibre measurement—a new technique of assessing Raynaud's phenomenon. Eur. J. Vasc. Surg. 5, 199–203 (1991).

    Article  CAS  PubMed  Google Scholar 

  59. Naidu, S., Baskerville, P. A., Goss, D. E. & Roberts, V. C. Raynaud's phenomenon and cold stress testing: a new approach. Eur. J. Vasc. Surg. 8, 567–573 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Chotani, M. A., Flavahan, S., Mitra, S., Daunt, D. & Flavahan, N. A. Silent α2C-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am. J. Physiol. Heart Circ. Physiol. 278, H1075–H1083 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Thompson-Torgerson, C. S., Holowatz, L. A., Flavahan, N. A. & Kenney, W. L. Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Am. J. Physiol. Heart Circ. Physiol. 292, H1700–H1705 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Bailey, S. R., Eid, A. H., Mitra, S., Flavahan, S. & Flavahan, N. A. Rho kinase mediates cold-induced constriction of cutaneous arteries: role of α2C-adrenoceptor translocation. Circ. Res. 94, 1367–1374 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Bailey, S. R., Mitra, S., Flavahan, S. & Flavahan, N. A. Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am. J. Physiol. Heart Circ. Physiol. 289, H243–H250 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Freedman, R. R., Baer, R. P. & Mayes, M. D. Blockade of vasospastic attacks by α2-adrenergic but not α1-adrenergic antagonists in idiopathic Raynaud's disease. Circulation 92, 1448–1451 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Fleming, I. Molecular mechanisms underlying the activation of eNOS. Pflugers Arch. 459, 793–806 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Ringqvist, A., Jonason, T., Leppert, J. & Ringqvist, I. Non-invasive investigation of endothelium-dependent dilatation of the brachial artery in women with primary Raynaud's phenomenon. Clin. Sci. (Lond.) 94, 239–243 (1998).

    Article  CAS  Google Scholar 

  67. Marasini, B. & Conciato, L. Iontophoretic evaluation of vascular reactivity to acetylcholine in patients with primary Raynaud's phenomenon and systemic sclerosis. Clin. Rheumatol. 20, 451–452 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Anderson, M. E., Moore, T. L., Lunt, M. & Herrick, A. L. Digital iontophoresis of vasoactive substances as measured by laser Doppler imaging—a non-invasive technique by which to measure microvascular dysfunction in Raynaud's phenomenon. Rheumatology (Oxford) 43, 986–991 (2004).

    Article  CAS  Google Scholar 

  69. Goel, A. et al. Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries. Circ. Res. 107, 242–251 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chauhan, A. K. et al. ADAMTS13: a new link between thrombosis and inflammation. J. Exp. Med. 205, 2065–2074 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Konttinen, Y. T. et al. Vascular damage and lack of angiogenesis in systemic sclerosis skin. Clin. Rheumatol. 22, 196–202 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Herrick, A. L. et al. Von Willebrand factor, thrombomodulin, thromboxane, β-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis. Ann. Rheum. Dis. 55, 122–127 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Marasini, B., Cugno, M. & Agostoni, A. Plasma levels of tissue-type plasminogen activator and von Willebrand factor in patients with Raynaud's phenomenon. Arthritis Rheum. 34, 255–256 (1991).

    Article  CAS  PubMed  Google Scholar 

  74. Vancheeswaran, R., Azam, A., Black, C. & Dashwood, M. R. Localization of endothelin-1 and its binding sites in scleroderma skin. J. Rheumatol. 21, 1268–1276 (1994).

    CAS  PubMed  Google Scholar 

  75. Rychlik-Golema, W., Mastej, K. & Adamiec, R. The role of endothelin-1 and selected cytokines in the pathogenesis of Raynaud's phenomenon associated with systemic connective tissue diseases. Int. Angiol. 25, 221–227 (2006).

    CAS  PubMed  Google Scholar 

  76. Vancheeswaran, R. et al. Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J. Rheumatol. 21, 1838–1844 (1994).

    CAS  PubMed  Google Scholar 

  77. Wigley, F. M. & Herrick, A. L. in Scleroderma: From Pathogenesis to Comprehensive Management (eds Varga, J. et al.) 313–329 (Springer, 2012).

    Book  Google Scholar 

  78. Korn, J. H. et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 50, 3985–3993 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Matucci-Cerinic, M. et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 70, 32–38 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Nguyen, V. A. et al. Effect of the dual endothelin receptor antagonist bosentan on Raynaud's phenomenon secondary to systemic sclerosis: a double-blind prospective, randomized, placebo-controlled pilot study. Rheumatology (Oxford) 49, 583–587 (2010).

    Article  CAS  Google Scholar 

  81. Freedman, R. R., Girgis, R. & Mayes, M. D. Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma. J. Rheumatol. 28, 119–121 (2001).

    CAS  PubMed  Google Scholar 

  82. Abou-Raya, A., Abou-Raya, S. & Helmii, M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers. J. Rheumatol. 35, 1801–1808 (2008).

    CAS  PubMed  Google Scholar 

  83. Rollando, D. et al. Brachial artery endothelial-dependent flow-mediated dilation identifies early-stage endothelial dysfunction in systemic sclerosis and correlates with nailfold microvascular impairment. J. Rheumatol. 37, 1168–1173 (2010).

    Article  PubMed  Google Scholar 

  84. Kovacic, J. C., Mercader, N., Torres, M., Boehm, M. & Fuster, V. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation 125, 1795–1808 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Piera-Velazquez, S., Li, Z. & Jimenez, S. A. Role of endothelial–mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am. J. Pathol. 179, 1074–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Trojanowska, M. Cellular and molecular aspects of vascular dysfunction in systemic sclerosis. Nat. Rev. Rheumatol. 6, 453–460 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Garcia, J. et al. Tie1 deficiency induces endothelial–mesenchymal transition. EMBO Rep. 13, 431–439 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Widyantoro, B. et al. Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121, 2407–2418 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Basile, D. P. et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am. J. Physiol. Renal Physiol. 300, F721–F733 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Maleszewska, M. et al. IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner. Immunobiology 218, 443–454 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Arciniegas, E., Frid, M. G., Douglas, I. S. & Stenmark, K. R. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L1–L8 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Riemekasten, G. et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann. Rheum. Dis. 70, 530–536 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Stawski, L., Han, R., Bujor, A. M. & Trojanowska, M. Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis. Arthritis Res. Ther. 14, R194 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jimenez, S. A. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatol. 2013, 835948 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Xu, H. et al. Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis. Am. J. Physiol. Cell. Physiol. 300, C550–C556 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. van Marken Lichtenbelt, W. Brown adipose tissue and the regulation of nonshivering thermogenesis. Curr. Opin. Clin. Nutr. Metab. Care 15, 547–552 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Tam, C. S., Lecoultre, V. & Ravussin, E. Brown adipose tissue: mechanisms and potential therapeutic targets. Circulation 125, 2782–2791 (2012).

    Article  PubMed  Google Scholar 

  100. McKemy, D. D. The molecular and cellular basis of cold sensation. ACS Chem. Neurosci. 4, 238–247 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. McCoy, D. D., Knowlton, W. M. & McKemy, D. D. Scraping through the ice: uncovering the role of TRPM8 in cold transduction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1278–R1287 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dhaka, A., Earley, T. J., Watson, J. & Patapoutian, A. Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28, 566–575 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Takashima, Y. et al. Diversity in the neural circuitry of cold sensing revealed by genetic axonal labelling of transient receptor potential melastatin 8 neurons. J. Neurosci. 27, 14147–14157 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Tajino, K. et al. Cooling-sensitive TRPM8 is thermostat of skin temperature against cooling. PLoS ONE 6, e17504 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tajino, K. et al. Application of menthol to the skin of whole trunk in mice induces autonomic and behavioural heat-gain responses. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R2128–R2135 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Knowlton, W. M., Daniels, R. L., Palkar, R., McCoy, D. D. & McKemy, D. D. Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS ONE 6, e25894 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Almeida, M. C. et al. Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioural cold defences and decreases deep body temperature. J. Neurosci. 32, 2086–2099 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chang, L., Milton, H., Eitzman, D. T. & Chen, Y. E. Paradoxical roles of perivascular adipose tissue in atherosclerosis and hypertension. Circ. J. 77, 11–18 (2013).

    Article  PubMed  Google Scholar 

  109. Chang, L. et al. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation 126, 1067–1078 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Johnson, C. D. et al. Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone. Am. J. Physiol. Heart Circ. Physiol. 296, H1868–H1877 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Greenstein, D., Jeffcote, N., Ilsley, D. & Kester, R. C. The menstrual cycle and Raynaud's phenomenon. Angiology 47, 427–436 (1996).

    Article  CAS  PubMed  Google Scholar 

  112. Wise, R. A. et al. Efficacy and tolerability of a selective α2C-adrenergic receptor blocker in recovery from cold-induced vasospasm in scleroderma patients: a single-center, double-blind, placebo-controlled, randomized crossover study. Arthritis Rheum. 50, 3994–4001 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Herrick, A. L. et al. A double-blind, randomized, placebo-controlled crossover trial of the α2C-adrenoceptor antagonist ORM-12741 for prevention of cold-induced vasospasm in patients with systemic sclerosis. Rheumatology (Oxford) 53, 948–952 (2014).

    Article  CAS  Google Scholar 

  114. Zhou, Q. & Liao, J. K. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ. J. 74, 818–826 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tuuminen, R. et al. Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection. Circulation 124, 1138–1150 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Furukawa, S. et al. Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis: a pilot study. Ann. Rheum. Dis. 65, 1118–1120 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kuwana, M. et al. Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis. Arthritis Rheum. 54, 1946–1951 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Fava, A. et al. Efficacy of Rho kinase inhibitor fasudil in secondary Raynaud's phenomenon. Arthritis Care Res. (Hoboken) 64, 925–929 (2012).

    Article  CAS  Google Scholar 

  119. Thompson-Torgerson, C. S., Holowatz, L. A., Flavahan, N. A. & Kenney, W. L. Rho kinase-mediated local cold-induced cutaneous vasoconstriction is augmented in aged human skin. Am. J. Physiol. Heart Circ. Physiol. 293, H30–H36 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Neumeister, M. W. et al. Botox therapy for ischemic digits. Plast. Reconstr. Surg. 124, 191–201 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Van Beek, A. L., Lim, P. K., Gear, A. J. & Pritzker, M. R. Management of vasospastic disorders with botulinum toxin A. Plast. Reconstr. Surg. 119, 217–226 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Fregene, A., Ditmars, D. & Siddiqui, A. Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud's phenomenon. J. Hand Surg. Am. 34, 446–452 (2009).

    Article  PubMed  Google Scholar 

  123. Montal, M. Botulinum neurotoxin: a marvel of protein design. Annu. Rev. Biochem. 79, 591–617 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Shibasaki, M. et al. Neurally mediated vasoconstriction is capable of decreasing skin blood flow during orthostasis in the heat-stressed human. J. Physiol. 575, 953–959 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Morris, J. L., Jobling, P. & Gibbins, I. L. Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons. Am. J. Physiol. Heart Circ. Physiol. 281, H2124–H2132 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Smyth, L. M., Breen, L. T. & Mutafova-Yambolieva, V. N. Nicotinamide adenine dinucleotide is released from sympathetic nerve terminals via a botulinum neurotoxin A-mediated mechanism in canine mesenteric artery. Am. J. Physiol. Heart Circ. Physiol. 290, H1818–H1825 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Niles, W. D. & Malik, A. B. Endocytosis and exocytosis events regulate vesicle traffic in endothelial cells. J. Membr. Biol. 167, 85–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Ma, S. et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. J. Mol. Cell Biol. 4, 88–96 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Wigley, F. M., Wise, R. A., Mikdashi, J., Schaefer, S. & Spence, R. J. The post-occlusive hyperemic response in patients with systemic sclerosis. Arthritis Rheum. 33, 1620–1625 (1990).

    Article  CAS  PubMed  Google Scholar 

  130. Cooke, J. P., Creager, M. A., Osmundson, P. J. & Shepherd, J. T. Sex differences in control of cutaneous blood flow. Circulation 82, 1607–1615 (1990).

    Article  CAS  PubMed  Google Scholar 

  131. Freedman, R. R. & Moten, M. Gender differences in modulation of peripheral vascular adrenoceptors. Ann. Behav. Med. 17, 15–18 (1995).

    Article  CAS  PubMed  Google Scholar 

  132. Bartelink, M. L., De Wit, A., Wollersheim, H., Theeuwes, A. & Thien, T. Skin vascular reactivity in healthy subjects: influence of hormonal status. J. Appl. Physiol. 74, 727–732 (1993).

    Article  CAS  PubMed  Google Scholar 

  133. Bartelink, M. L., Wollersheim, H., Theeuwes, A., van Duren, D. & Thien, T. Changes in skin blood flow during the menstrual cycle: the influence of the menstrual cycle on the peripheral circulation in healthy female volunteers. Clin. Sci. (Lond.) 78, 527–532 (1990).

    Article  CAS  Google Scholar 

  134. Eid, A. H. et al. Estrogen increases smooth muscle expression of α2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am. J. Physiol. Heart Circ. Physiol. 293, H1955–H1961 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Kim, H., Richardson, C., Roberts, J., Gren, L. & Lyon, J. L. Cold hands, warm heart. Lancet 351, 1492 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nicholas A. Flavahan.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Flavahan, N. A vascular mechanistic approach to understanding Raynaud phenomenon. Nat Rev Rheumatol 11, 146–158 (2015). https://doi.org/10.1038/nrrheum.2014.195

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2014.195

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing