Involvement of Rho‐kinase in hypertensive vascular disease —a novel therapeutic target in hypertension

ABSTRACT Intracellular signaling pathway mediated by Rho/Rho‐kinase plays an important role in the regulation of vascular smooth muscle contraction and other cellular functions, including adhesion, migration, proliferation, and hypertrophy. A Rho‐kinase inhibitor has been shown to lower blood pressure in hypertensive rats in vivo, however, direct evidence for the involvement of Rho‐kinase in hypertensive vascular disease is still lacking. In this study, we tested our hypothesis that Rho‐kinase is involved substantially in functional and structural alterations of hypertensive blood vessels in spontaneously hypertensive rats (SHR). Force measurement with isolated blood vessels demonstrated that Rho‐kinase was involved significantly in the vascular hyperreactivity in SHR. Biochemical analysis showed that both the expression and the activity of Rho‐kinase were augmented in blood vessels of SHR. It is important to note that the involvement of Rho‐kinase in the vascular hyperreactivity preceded the development of hypertension. Finally, long‐term blockade of Rho‐kinase suppressed vascular lesion formation such as medial hepertrophy and perivascular fibrosis in SHR. Our results provide the first evidence that augmented expression and function of Rho‐kinase plays a key role in the pathogenesis of hypertensive vascular disease, which suggests that this molecule could be regarded as a novel therapeutic target in hypertension.