Signaling Pathways of Mechanotransduction in Arteriolar Endothelium and Smooth Muscle Cells in Hypertension

Hypertension, a disease with a high incidence in the population, affects all parts of the cardiovascular system. Studying the alteration of vasomotor responses of microvessels of hypertensive animals or responses of vessels following short-term increases in hemodynamic forces helps us to better understand the underlying cellular signaling events responsible for their functional adaptation. These adaptations are likely to precede the structural remodeling of arterioles, resulting in irreversible increases in peripheral vascular resistance in hypertension. Although malfunction of several mechanisms can lead to the development of hypertension, hemodynamic forces (such as pressure and shear stress) are increased in all forms of hypertension. Thus, local mechanisms that sense the level of these forces and transduce the signals into vasomotor responses must be affected in all forms of hypertension. The endothelium has a central role in the early functional adaptations. Pressure-induced myogenic constriction is enhanced due to the augmented release of endothelium-derived constrictor factors that modulate arteriolar smooth muscle sensitivity to Ca(2+). In contrast, flow/shear stress-induced dilation of arterioles is reduced in hypertension, due to the impaired mediation of the response by nitric oxide (NO). The magnitude of impairment is gender specific, primarily due to an estrogen-dependent enhancement of NO release in females. It is proposed that the elevated hemodynamic forces present in hypertension may themselves initiate these alterations, probably by enhancing the release of reactive oxygen species (ROS; produced by xanthine oxidase, NAD(P)H oxidoreductase, eNOS, etc.), which then interfere with the synthesis and/or action of endothelium-derived mediators. Interfering early on with these mechanisms may prevent the development of irreversible structural changes of the microcirculation observed in hypertension.