Abstract
Raynaud’s phenomenon (RP) is very often the first manifestation of SSc preceding the onset of all the other signs and symptoms of the disease. Two structures are involved in the pathogenesis of RP: the endothelium and the peripheral nervous system (PNS). The hypothesis is that SSc modifies consistently the activity of both these systems leading eventually to RP. The disease, through the injury to the endothelium, jeopardizes the basilar endothelial-dependent vascular tone control. An increase of endothelin, a potent endo- thelial-derived vasoconstrictor, and the reduction of nitric oxide, one of the main endothelial vasodilators, are two key events involved in the genesis of RP. The PNS is also targeted by the disease as demonstrated by the high incidence of neuropathy in SSc patients. A marked reduction of sensory fibres has been detected in SSc skin. Thus, the involvement of nerve terminals reduces the vasodilatory, endothelial dependent or independent, potential of the neuropeptides released by sensory nerve endings. Indeed, an increased sensitivity of α2 adrenoceptors mediated vasoconstriction has been shown in SSc skin. The complex vasodilatory network formed by the interaction between the endothelium and the PNS seems greatly damaged by SSc leading inesorably toward vascular tone dysfunction clinically evident as RP.
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References
Seibold JR.: Scleroderma. In Textbook of Rheumatology, (eds. W N Kelly, ED Harris, S Rudy, and CB Sledge, 1989, pp. 1215–44. WB Saunders, Philadelphia.
Campbell PM and Leroy EC: Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum 4: 351–68. 1975
LeRoy EC: Systemic sclerosis: A vascular perspective. Rheum Dis Clin N Am 22: 675–694. 1996
Fleischmajer R, Perlish JS: Capillary alterations in scleroderma. J AM Acad Dermatol 2: 161–70. 1980
Generini S, Kahaleh BM, Matucci Cerinic M, et al.: Raynaud’s phenomenon and systemic sclerosis. Ann Ital Med Int 11: 125–131. 1996
Pearson JD: The endothelium: its role in systemic sclerosis. Ann Rheum Dis 50, 866–71. 1991
Milner P, Ralevic V, Hopwood AM, Fehér E, Lincoln J, Kirpatrick KA, Burnstock G: Ultrastructural localisation of substance P and choline acetyltransferase in endothelial cells of rat coronary artery and release of substance P and acethycholine during hypoxia. Experientia 45: 121–125. 1989
Milner P, Kirpatrick K, Ralevic V, Toothill V, Pearson J, Burnstock G: Endothelial cells cultured from human umbilical vein release ATP substance P and acetylcholine in response to increased flow. Proc R Soc London B, 241: 245–248. 1990.
Prins BA, Hu RM, Nazario B, et al.: Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells. J Biol Chem 269: 11938–44. 1994
Boulanger C and Luscher TF: Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 85: 587–590. 1990
Warner TD, Mitchell JA, De Nucci G and Vane JR: Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit. J Cardiovasc Pharmacol 13: S85-S88. 1989
Miura K, Yukimura T, Yamashita Y, Shimmen T, et al.: Endothelin stimulates the renal production of prostaglandin E2 and I2 in anesthetized dogs. Eur J Pharmacol 170: 91–93. 1989
Miura K, Yukumura T, Yamashita Y, et al.: Renal and femoral vascular responses to endothelin-1 in dogs: role of prostaglandins. J Pharmacol Exp Ther 256: 11–17. 1991
Matucci-Cerinic M, Kahaleh MB, LeRoy EC. The vascular involvement in systemic sclerosis. In: “Systemic Sclerosis”, eds. PJ Clements and DE Furst, Baltomore 153–174. 1996
Kahaleh BM, Matucci-Cerinic M: Endothelial injury and its implication. In: “Thrombosis: an update”, eds. GG Neri Serneri, GF Gensini, R Abbate, D Prisco, Scientific Press, Florence, 649–658. 1992
Kahaleh BM: Lymphocyte interactions with the vascular endothelium in scleroderma. Clin Dermatol 12: 1994
Cohen S, Johnson AR, Hurd E: Cytotoxicity of sera from patients with scleroderma: effects on human endothelial cells and fibroblast in culture. Arthritis Rheum 26: 170–78. 1983
Kahaleh MB, Sherer GK, and LeRoy EC: Endothelial injury in scleroderma. J Exp Med 149: 1326–35. 1979
Kobayashi Y, Masuzawa M, Nishioka K and Sano S: Growth suppression of endothelial cells of the guinea pig aorta by the sera of patients with progressive systemic sclerosis. Nippon hifuka Gakkai Zasshi 94: 1639–1641. 1984
Penning CA, Cunnigham J, French MAH, et al.: Antibody-dependent cellular cytotoxicity of human vascular endothelium in systemic sclerosis. Clin Exp Immunol 58: 548–556. 1984
Shanahan WR Jr, Korn: Cytotoxic acivity of sera from scleroderma and other connective tissue diseases: lack of cellular and disease specificity. Arthritis Rheum 25 1391–1395. 1982
Summers GD, Weiss JB, Jayson MIV: Failure of sera from paients with scleroderma to exhibit cytotoxicity towards human umbilical vein endothelial cells. Rheumatol Int 5: 9–13. 1984
Marks RM, Czerniecki M, Andrews BS and Penny R: The effects of scleroderma serum on human microvascular endothelial cells. Arthritis Rheum 31: 1524–34. 1988
Kanaleh BM and Yin T: The molecular mechanism of endothelial cell injury in scleroderma. Identification of granzyme 1 (a product of cytolytic T cell) in SSc sera. Arthritis Rheum 33: s21. 1992
Kahaleh BM and Fan PS: Ctotoxic T cel involvement in scleroderma: detection of granzyme a gene expression in systemic sclerosis skin. Arthritis Rheum 35: s22. 1992
Kahaleh BM and LeRoy EC: Endothelial injury in scleroderma: a protease mechanism. J Lab Clin Med 101: 553–557. 1983
Pasternak MS, Verret CR, Liu MA and Eisen HN: Serine esterase in cytotoxic T lymphocytes. Nature 322: 740. 1986
Kahaleh MB, Osborn I and LeRoy EC: Increased Factor VIII/von Willebrand factor antigen and von Wille-brand factor activity in scleroderma and in Raynaud’s phenomenon. Ann Int Med 94: 482. 1981
Godin-Ostro E, Mitrane M, Heller I, et al.: Plasma plasminogen activator in systemic sclerosis. Arthritis Rheum 28 (suppl 4): s80. 1985
Matucci-Cerinic M, Pignone A, Lotti T, et al.: Reduced angiotensin converting enzyme plasma activity in scleroderma. A marker of endothelial injury? J Rheumatol 17: 328–30. 1990
Matucci-Cerinic M, Pietrini U, Marabini S. Local venomotor response to intravenous infusion of substance P and glyceryl trinitrate in systemic sclerosis. Clin Exp Rheumatol 8: 561–565. 1990
BM Kahaleh, Pan-Sheng F, Matucci Cerinic M, Stefanovic Racic M, Ignarro L: Study of endothelial dependent relaxation in scleroderma. Arthritis Rheum 36 (suppl): B233. 1993
Kahaleh BM: Endothelin and endothelial dependent vasoconstrictor in scleroderma. Arthritis Rheum 34: 978–983. 1991
Yamane K, Kashiwagi H, Suzuki N, et al.: Elevated plasma levels of endothelin-1 in systemic sclerosis. Arthritis Rheum 34: 243. 1991
Yamane K, Miyouchi T, Suzuki N, et al.: Significance of plasma endothelin 1 levels in patients with systemic sclerosis. J Rheumatol 19: 1566–70. 1992
Vancheeswaran R, Magoulas T, Efrat G, Wheeler-Jones C, Olsen I, Penny R, Black CM: Circulating endothelin 1 levels in systemic sclerosis: a marker of fibrosis of vascualr dysfumction. J Rheumatol 21: 1838–44. 1994
Kanno K, Hirata Y, Emori T, et al.: Endothelin and Raynaud’s phenomenon. Am J Med 90: 130–2. 1991
Evans CE, Patel MKN, Thompson R, Mc Evoy FA, Jayson MIV: Prostacyclin levels in systemic sclerosis. In “Current topics in Rheumatology: systemic sclerosis”. Black C, Myers AR, eds. New York: Gower, 264–266. 1985
Holt CM, Lindsey MN, Hughes P, et al.: Prostacyclin production by human umbilical vein endothelium in response to serum from patients with systemic sclerosis. Br J Rheum 28: 216–220. 1989
Lindsey N, Henderson F, Malia R, Greaves M and Hughes P: Serum masks the inhibition of thrombin-in-duced prostacyclin release produced by anticardiolipin antibodies. Br J Rheum 31: 179–183. 1992
Rustin MHA, Bull HA, Machin SJ, et al.: Serum from patients with Raynaud’s phenomenon inhibits prostacyclin production. J Invest Dermatol 89: 555–559. 1987
Belch JJF, McLaren M, Anderson J, et al.: Increased prostacyclin metabolites and decreased red cell deformability in patients with systemic sclerosis and Raynaud’s syndrome. Prostaglandins Leuko Essent Fatty Acids, 17: 1–9. 1985
Reilly IAG, Roy L, Fitzgerald GA: Biosynthesis of thromboxane in patients with systemic sclerosis and Raynaud’s phenomenon. Br Med J, 292: 1037–1039. 1986
Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362: 801–809. 1993
Hietaharju A, Jaaskelainen S, Kalimo H, Hietarinta M: Peripheral neuromuscular manifestations in systemic sclerosis (scleroderma). Muscle Nerve Nov; 16: 1204–1212. 1993
Lori S, Matucci Cerinic M, Casale R, et al.: Peripheral nervous system involvement in systemic sclerosis: the median nerve as a target structure. Clin Exp Rheumatol; 14: 601–605. 1996
Matucci Cerinic M, Generini S, Pignone A, Casale R: The nervous system in systemic sclerosis (scleroderma). Rheum Dis Clin N Am 22: 879–892. 1996
Dessein PHMC, Joffe BL, Metz RM, et al.: Autonomic dysfunction in systemic sclerosis: Sympathetic overactivity and instability. Am J Med; 93: 143–150. 1992
Klimiuk PS, Taylor L, Baker RD, et al.: Autonomic neuropathy in systemic sclerosis. Ann Rheum Dis 47: 542–545. 1988
Jamieson GG, Ludbrook J, Wilson A. Cold hypersensitivity in Raynaud’s phenomenon. Circulation 44: 254–264. 1971
Freedman RR, Moten M, Migaly P, Mayes M. Cold-induced potentiation of alpha 2-adrenergic vasoconstriction in primary Raynaud’s disease. Arthritis Rheum 36: 685–690. 1993
Burnstock G. Mechanism of action of peptide and non peptide vascular neurotransmitter system. J Cardiovasc Pharmacol 12 (suppl): S74–81. 1987
Matucci-Cerinic M. Sensory neuropeptides and rheumatic diseases. Rheum Dis Clin N Am 19: 975–991. 1993
M Matucci-Cerinic, S Marroccu, P Cappugi, et al.: Reduced vasodilatory response in systemic sclerosis. Arthritis Rheum 38 (Suppl): 837. 1995
Murrell DF: A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol 28: 78–85. 1993
Blann AD, Illingworth K, Jayson MIV: Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud’s Phenomenon. J Rheumatol 20: 1325–1330. 1993
Bruckdorfer KR, Hillary JB, Bunce T, Vancheeswaran R, Black CM: Increased susceptibility to oxidation of low density lipoproteins isolated from patients with systemic sclerosis. Arthritis Rheum 38: 1060–1067. 1995
Lundberg AC, Akesson A, Akesson B: Dietary intake and nutritional status in patients with systemic sclerosis. Ann Rheum Dis 51: 1143–1148. 1992
Stein CM, Tanner SB, Awad JA, Roberts II LJ, Morrow, JD: Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthitis Rheum 39: 1146–1150. 1996
Herrick AL, Worthington H, Rieley F, Clarke D, Schofield D, Braganza JM, Jayson MIV: Dietary intake of micronutrient antioxidant in relation to blood levels in patients with systemic sclerosis. J Rheumatol 23: 650–653. 1996
Herrick AL, Rieley F, Braganza JM, Jayson MIV: Difficulty in detecting reperfusion injury increment in oxidative stress among patients with primary Raynaud’s phenomenon and systemic sclerosis. J Rheumatol 22: 374–375. 1995
Morita A, Minami H, Sakakibara N, Sato K, Tsuji T AD: Elevated plasma Superoxide dismutase activity in patients with systemic sclerosis. J Dermatol Sci 11: 196–201. 1996
Casciola-Rosen L, Wigley F, Rosen A: Scleroderma autoantigens are uniquely fragmented by metal catalyzed oxidation reactions: implications for pathogenesis. J Exp Med 185: 71–79. 1997
Das DK, Engelman R, Cherian KM: Myocardial preservation, preconditioning and adaptation. NY Acad Sci 793: 1–533. 1996
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Generini, S., Cerinic, M.M. (1999). Raynaud’s Phenomenon and Vascular Disease in Systemic Sclerosis. In: Mallia, C., Uitto, J. (eds) Rheumaderm. Advances in Experimental Medicine and Biology, vol 455. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4857-7_13
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