Scleroderma (SSc) is a disease of unknown etiology associated with high mortality and morbidity. An early feature of SSc is reversible vasospasm occurring in peripheral, myocardial, renal and pulmonary circulations - Raynaud's phenomenon is present in 95 percent of cases. Small arteries/arterioles subsequently develop concentric intimal thickening and adventitial fibrosis. In preliminary studies, small dermal arteries (100-300 mu diameter) were isolated from skin biopsies of SSc patients and from age/sex-matched controls and mounted in a microperfusion system. Vascular smooth muscle of SSc arteries (clinically-uninvolved skin) demonstrated a dramatic and selective increase (300-fold) in contractile reactivity to stimulation of alpha2- adenoceptors (alpha2-ARs). Endothelial function, as assessed by NO- mediated, endothelium-dependent relaxation to acetylcholine or bradykinin, was normal. In SSc arteries from involved skin, endothelium-dependent response to bradykinin was impaired suggesting the presence of endothelial dysfunction. The hypothesis of this proposal is that an early feature of SSc is an increased reactivity of microvascular smooth muscle alpha2-ARs. This causes inappropriate and exaggerated vasoconstriction in response to physiologic stimuli (e.g. nerve stimulation, cold). The resulting cycles of ischemia and reperfusion, characteristic of SSc, leads to dysfunction of microvascular endothelial cells, promoting vascular lesion development and the extravascular complications of the disease process. To test this hypothesis, experiments will be performed on isolated dermal arteries from subjects with SSc or primary Raynaud's disease, and from age/sex matched controls. Pharmacological, biochemical and molecular techniques will be used to address 3 specific aims: 1) to determine the mechanisms(s) underlying increased responsiveness to alpha-AR stimulation in SSc, 2) to determine whether the neural regulation of SSc microvascular contraction is dysfunctional, and 3) to analyze endothelial function, and the mechanisms underlying development of endothelial dysfunction in SSc. These studies should increase our understanding of the SSc disease process and may provide a scientific basis for therapeutic intervention.
