Pathogenesis of the Raynaud phenomenon
- Fredrick M Wigley, MD
Fredrick M Wigley, MD
- Professor of Medicine
- Johns Hopkins University School of Medicine
One of the normal physiologic responses to cold temperature is the lowering of blood flow to the skin, thereby reducing the loss of body heat and preserving normal core temperature. Blood flow to the skin is regulated by a complex interactive system involving neural signals, circulating hormones, and mediators released from both circulating cells and blood vessels.
Raynaud phenomenon (RP) is an exaggerated vascular response to cold temperature or emotional stress. The phenomenon is manifested clinically by sharply demarcated color changes of the skin of the digits. Abnormal vasoconstriction of digital arteries and cutaneous arterioles due to a local defect in normal vascular responses is thought to underlie the primary form of this disorder [1-4].
RP is considered primary if these symptoms occur alone without evidence of any associated disorder. By comparison, secondary disease refers to the presence of RP in association with a related illness, such as systemic lupus erythematosus and systemic sclerosis (SSc).
The pathogenesis of RP will be reviewed here. The definition, clinical manifestations, diagnosis, and treatment of the disorder are presented separately. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon" and "Initial treatment of the Raynaud phenomenon" and "Treatment of the Raynaud phenomenon resistant to initial therapy".)
Maurice Raynaud in 1862 stated that "local asphyxia of the extremities" was a result of "increased irritability of the central parts of the cord presiding over the vascular innervation" . In 1930, after observing that even when reflex vasodilation is produced by warming the body, vasospasm could still be induced by putting the hands in cold water, and conversely, that vasospasm could not be produced by body cooling if the hands were kept warm, Sir Thomas Lewis concluded that Raynaud phenomenon (RP) was due to a "local fault" rather than a defect in the central nervous system . A local defect(s) is hypothesized to be responsible for RP. However, the exact abnormality may vary depending upon the underlying cause .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Boin F, Wigley FM. Understanding, assessing and treating Raynaud's phenomenon. Curr Opin Rheumatol 2005; 17:752.
- Block JA, Sequeira W. Raynaud's phenomenon. Lancet 2001; 357:2042.
- Wigley FM. Clinical practice. Raynaud's Phenomenon. N Engl J Med 2002; 347:1001.
- Flavahan NA. A vascular mechanistic approach to understanding Raynaud phenomenon. Nat Rev Rheumatol 2015; 11:146.
- Raynaud, M. Local asphyxia and symmetrical gangrene of the extremities 1862. New researches on the nature and treatment of local asphyxia of the extremities 1874. Translated by Barlow London: New Syndenham Society,1888.
- Lewis T. Experiments relating to the peripheral mechanism involved in spasmodic arrest of the circulation of the fingers. A variety of Raynaud's disease. Heart 1929; 14:7.
- Herrick AL. Pathogenesis of Raynaud's phenomenon. Rheumatology (Oxford) 2005; 44:587.
- McKemy DD. How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation. Mol Pain 2005; 1:16.
- Schepers RJ, Ringkamp M. Thermoreceptors and thermosensitive afferents. Neurosci Biobehav Rev 2010; 34:177.
- McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002; 416:52.
- Almeida MC, Hew-Butler T, Soriano RN, et al. Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J Neurosci 2012; 32:2086.
- Charkoudian N. Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc 2003; 78:603.
- Generini S, Seibold JR, Matucci-Cerinic M. Estrogens and neuropeptides in Raynaud's phenomenon. Rheum Dis Clin North Am 2005; 31:177.
- Flavahan NA, Vanhoutte PM. Effect of cooling on alpha-1 and alpha-2 adrenergic responses in canine saphenous and femoral veins. J Pharmacol Exp Ther 1986; 238:139.
- Flavahan NA, Flavahan S, Mitra S, Chotani MA. The vasculopathy of Raynaud's phenomenon and scleroderma. Rheum Dis Clin North Am 2003; 29:275.
- Flavahan NA, Vanhoutte PM. Endothelial cell signaling and endothelial dysfunction. Am J Hypertens 1995; 8:28S.
- Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83:1774.
- Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109.
- Kirchengast M, Münter K. Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. Proc Soc Exp Biol Med 1999; 221:312.
- 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 2006; 25:221.
- Herrick AL, Illingworth K, Blann A, et al. Von Willebrand factor, thrombomodulin, thromboxane, beta-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis. Ann Rheum Dis 1996; 55:122.
- Fraenkel L, Zhang Y, Chaisson CE, et al. The association of estrogen replacement therapy and the Raynaud phenomenon in postmenopausal women. Ann Intern Med 1998; 129:208.
- Lekakis J, Papamichael C, Mavrikakis M, et al. Effect of long-term estrogen therapy on brachial arterial endothelium-dependent vasodilation in women with Raynaud's phenomenon secondary to systemic sclerosis. Am J Cardiol 1998; 82:1555.
- Lekakis J, Mavrikakis M, Papamichael C, et al. Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud's phenomenon. Am Heart J 1998; 136:905.
- Eid AH, Maiti K, Mitra S, et al. Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 2007; 293:H1955.
- Flavahan NA, Cooke JP, Shepherd JT, Vanhoutte PM. Human postjunctional alpha-1 and alpha-2 adrenoceptors: differential distribution in arteries of the limbs. J Pharmacol Exp Ther 1987; 241:361.
- Coffman JD, Cohen RA. Role of alpha-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits. Eur J Clin Invest 1988; 18:309.
- Ekenvall L, Lindblad LE, Norbeck O, Etzell BM. alpha-Adrenoceptors and cold-induced vasoconstriction in human finger skin. Am J Physiol 1988; 255:H1000.
- Coffman JD, Cohen RA. Alpha-2-adrenergic and 5-HT2 receptor hypersensitivity in Raynaud's disease. J Vasc Med Biol 1990; 2:100.
- Freedman RR, Baer RP, Mayes MD. Blockade of vasospastic attacks by alpha 2-adrenergic but not alpha 1-adrenergic antagonists in idiopathic Raynaud's disease. Circulation 1995; 92:1448.
- Freedman RR, Moten M, Migály P, Mayes M. Cold-induced potentiation of alpha 2-adrenergic vasoconstriction in primary Raynaud's disease. Arthritis Rheum 1993; 36:685.
- Lindblad LE, Ekenvall L, Etzell BM, Bevegård S. Adrenoceptors in Raynaud's disease. J Cardiovasc Pharmacol 1989; 14:881.
- Chotani MA, Flavahan S, Mitra S, et al. Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol 2000; 278:H1075.
- Kristensen JK, Engelhart M, Nielsen T. Laser-Doppler measurement of digital blood flow regulation in normals and in patients with Raynaud's phenomenon. Acta Derm Venereol 1983; 63:43.
- Sawasaki N, Iwase S, Mano T. Effect of skin sympathetic response to local or systemic cold exposure on thermoregulatory functions in humans. Auton Neurosci 2001; 87:274.
- Chotani MA, Mitra S, Su BY, et al. Regulation of alpha(2)-adrenoceptors in human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2004; 286:H59.
- Bailey SR, Eid AH, Mitra S, et al. Rho kinase mediates cold-induced constriction of cutaneous arteries: role of alpha2C-adrenoceptor translocation. Circ Res 2004; 94:1367.
- Bailey SR, Mitra S, Flavahan S, Flavahan NA. Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 2005; 289:H243.
- Furspan PB, Chatterjee S, Mayes MD, Freedman RR. Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon. Rheumatology (Oxford) 2005; 44:488.
- Furspan PB, Chatterjee S, Freedman RR. Increased tyrosine phosphorylation mediates the cooling-induced contraction and increased vascular reactivity of Raynaud's disease. Arthritis Rheum 2004; 50:1578.
- Zamora MR, O'Brien RF, Rutherford RB, Weil JV. Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon. Lancet 1990; 336:1144.
- Bunker CB, Terenghi G, Springall DR, et al. Deficiency of calcitonin gene-related peptide in Raynaud's phenomenon. Lancet 1990; 336:1530.
- Knock GA, Terenghi G, Bunker CB, et al. Characterization of endothelin-binding sites in human skin and their regulation in primary Raynaud's phenomenon and systemic sclerosis. J Invest Dermatol 1993; 101:73.
- Bottomley W, Goodfield M. A pathogenic role for endothelin in Raynaud's phenomenon? Acta Derm Venereol 1994; 74:433.
- Khan F, Coffman JD. Enhanced cholinergic cutaneous vasodilation in Raynaud's phenomenon. Circulation 1994; 89:1183.
- 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) 1998; 94:239.
- de Trafford JC, Lafferty K, Potter CE, et al. An epidemiological survey of Raynaud's phenomenon. Eur J Vasc Surg 1988; 2:167.
- Planchon B, Pistorius MA, Beurrier P, De Faucal P. Primary Raynaud's phenomenon. Age of onset and pathogenesis in a prospective study of 424 patients. Angiology 1994; 45:677.
- Freedman RR, Mayes MD. Familial aggregation of primary Raynaud's disease. Arthritis Rheum 1996; 39:1189.
- MacGregor AJ, Cherkas LJ, Carter L, et al. The genetic contribution to Raynaud's phenomenon: a population-based twin study. Arthritis Rheum 1999; 42:S233.
- Susol E, MacGregor AJ, Barrett JH, et al. A two-stage, genome-wide screen for susceptibility loci in primary Raynaud's phenomenon. Arthritis Rheum 2000; 43:1641.
- Wigley FM. Vascular disease in scleroderma. Clin Rev Allergy Immunol 2009; 36:150.
- Blann AD, Illingworth K, Jayson MI. Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud's phenomenon. J Rheumatol 1993; 20:1325.
- Freemont AJ, Hoyland J, Fielding P, et al. Studies of the microvascular endothelium in uninvolved skin of patients with systemic sclerosis: direct evidence for a generalized microangiopathy. Br J Dermatol 1992; 126:561.
- Kazandjian S, Fiessinger JN, Camilleri JP, et al. Endothelial cell renewal in skin of patients with progressive systemic sclerosis (PSS): an in vitro autoradiographic study. Acta Derm Venereol 1982; 62:425.
- Pearson JD. The endothelium: its role in scleroderma. Ann Rheum Dis 1991; 50 Suppl 4:866.
- Prescott RJ, Freemont AJ, Jones CJ, et al. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166:255.
- Matucci Cerinic M, Kahaleh MB. Beauty and the beast. The nitric oxide paradox in systemic sclerosis. Rheumatology (Oxford) 2002; 41:843.
- Flavahan NA, Flavahan S, Liu Q, et al. Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma. Arthritis Rheum 2000; 43:1886.
- Fleischmajer R, Perlish JS. [3H]Thymidine labeling of dermal endothelial cells in scleroderma. J Invest Dermatol 1977; 69:379.
- Kahaleh MB. Endothelin, an endothelial-dependent vasoconstrictor in scleroderma. Enhanced production and profibrotic action. Arthritis Rheum 1991; 34:978.
- Vancheeswaran R, Azam A, Black C, Dashwood MR. Localization of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 1994; 21:1268.
- Freedman RR, Girgis R, Mayes MD. Acute effect of nitric oxide on Raynaud's phenomenon in scleroderma. Lancet 1999; 354:739.