Vascular Stiffening Mediated by Rho‐Associated Coiled‐Coil Containing Kinase Isoforms

BACKGROUND: The pathogenesis of vascular stiffening and hypertension is marked by non‐compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho‐associated coiled‐coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known. METHODS AND RESULTS: Hemizygous Rock mice (Rock1 (+/−) and Rock2 (+/−)) were used to determine the role of ROCK1 and ROCK2 in age‐related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild‐type mice compared with that of Rock1 (+/−) and Rock2 (+/−) mice. As a model for age‐related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L‐N(ω)‐nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12‐week‐old male Rock1 (+/−) and Rock2 (+/−) mice. Similar to advancing age, angiotensin II/L‐N(ω)‐nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in Rock2 (+/−), and to a lesser extent, Rock1 (+/−) mice. The reduction of aortic stiffening in Rock2 (+/−) mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor‐β1 or angiotensin II was greatly attenuated in Rock2 (−/−) mouse embryonic fibroblasts. CONCLUSIONS: These findings indicate that ROCK1 and ROCK2 mediate both age‐related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age‐related vascular stiffening.