Angiotensin and cytoskeletal proteins: role in vascular remodeling.

Vascular remodeling occurs during normal development and is involved in various physiologic events. However, the adaptive structural changes of the vasculature can also be pathologic, leading to vascular disease such as hypertension, atherosclerosis, and vein graft disease. Pre-eclampsia may develop as a consequence of inappropriate vascular remodeling during pregnancy. Angiotensin II contributes to vascular remodeling by activating signal transduction cascades that promote vasoconstriction, growth, and inflammation. The cytoskeleton also participates in structural adaptation responses of the vasculature; cytoskeletal filaments may mediate vasoactive responses, transduce mechanical stimuli, and are involved in pharmacologic signal transduction. It has become clear that many of the cytoskeletal changes during vascular remodeling can be induced by angiotensin II. Recently, the small G-protein Rho has attracted much attention. The Rho/Rho-kinase system is activated by angiotensin II, is a prominent regulator of the cytoskeleton, and is involved in pathologic vascular remodeling.

Role of the Rhoa/Rho kinase system in flow-related remodeling of rat mesenteric small arteries in vivo.

In small arteries, a chronic blood flow reduction leads to inward hypotrophic remodeling, while a chronic blood flow elevation induces outward hypertrophic remodeling. The RhoA/Rho kinase system was shown to be modulated by shear stress, and to be involved in other kinds of vascular remodeling. The aim of this study was to investigate the role of RhoA/Rho kinase in flow-related small artery remodeling. Rat mesenteric small arteries were subjected to flow-modifying surgery. After 1, 2, 4, 16, and 32 days, the animals were sacrificed and small arteries were harvested. Messenger RNA was isolated and amplified. Using cDNA microarray analysis, the differential expression of >14,000 genes was analyzed, part of which was confirmed by RT-PCR. In vivo treatment with fasudil (3 mg/kg/day s.c.) was used to test the effect of Rho kinase inhibition. The main findings are that: (1) blood flow alteration modified the expression of approximately 5% of the genes by >2-fold, (2) flow reduction downregulated many RhoA-related cytoskeletal markers of smooth muscle cell phenotype, (3) many RhoA-related genes were rapidly (<1 day) regulated and (4) fasudil treatment potentiated the inward hypotrophic remodeling in response to chronically reduced flow. These results indicate the importance of the RhoA/Rho kinase system in flow-related small artery remodeling.