Rho/Rho-kinase signaling is implicated in the pathogenesis of various systemic vascular diseases (58). The Rho-kinase inhibitors Y-27632 and fasudil cause greater acute systemic vasodilation in hypertensive rats and patients than in their normotensive counterparts, implying an increased contribution of Rho-kinase-mediated Ca2+ sensitization to the regulation of systemic vascular tone in hypertension. Treatment with Rho-kinase inhibitors also prevents coronary artery medial hypertrophy and perivascular fibrosis in hypertensive rats (29, 39). 5-HT-induced vasospasm of coronary arteries is associated with hyperphosphorylation of MBS and MLC, and Rho-kinase inhibition prevents both the vasospasm and hyperphosphorylation (59). Fasudil reduces acetylcholine-induced coronary vasospasm in patients with vasospastic angina (36). In vivo gene transfer of dominant-negative Rho-kinase reverses IL-1P-coronary arteriosclerosis (38), and Rho-kinase inhibitors suppress neointimal formation after balloon injury (56).
In contrast to the considerable evidence for its involvement in systemic vascular diseases, there is little information on the importance of Rho/Rho-kinase signaling in the pathogenesis of pulmonary hypertension. Recent studies in our laboratory (16, 37, 42, 47) and others (1, 18, 22, 44) indicate that Rho/Rho-kinase signaling plays a role in both HPH and monocrotaline-induced pulmonary hypertension. However, a great deal remains to be learned about how, when, and where in the hypertensive pulmonary vasculature this pathway is activated and exactly what role(s) it plays, and by what mechanisms, in mediating increased vascular tone and remodeling.
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