To What Degree can Vascular Stiffness be Reversed by Overriding Signaling Changes?

Vascular stiffness causes hypertension and detrimental remodeling of the heart because it breaks all of the pressure-related feedback mechanisms in our cardiovascular system. Vascular stiffness is caused by mechanisms such as cross-linking in the extracellular matrix, and the inflammatory and other signals of senescent cells that promote calcification in blood vessel walls. The muscle responsible for blood vessel constriction is also involved in stiffening, however, and here we can ask to what degree this contribution is a reaction to the damage of aging, a change in the regulation of muscle tissue activity, rather than the direct result of molecular damage. Reactions can be overridden, even though that can never be as good a strategy as addressing the underlying causes. Sadly, most members of the research community seem very averse to addressing root causes in aging and disease - they are much more willing to tinker with the disease state or its proximate causes, as in the example here.

The progressive increase in blood pressure (BP) with age is characterized by a greater increase in isolated systolic hypertension, a larger elevation in systolic blood pressure (SBP) than diastolic blood pressure (DBP), leading to an accelerating rise in pulse pressure (PP). Although it is widely accepted that the increase in SBP with advancing age is mostly consistent with the large artery stiffening, there is still no consensus on what are the primary causes of these disorders. Our recent studies show that increased intrinsic stiffness of vascular smooth muscle cells (VSMCs) in aorta is an important contributor to the pathogenesis of aortic stiffening in both aging and hypertension, and that this could be a novel target for future anti-aortic stiffness drug development. However, less is known about molecular regulation involved in the VSMC stiffening in large arteries.

Rho-associated protein kinase (ROCK) is a serine/threonine protein kinase that has been identified as one of the effector of the small GTP-binding protein Rho. Although accumulating evidence has demonstrated that the ROCK pathway plays a crucial role in the pathogenesis of hypertension, ROCK has not previously been shown to be involved in cellular stiffening of VSMC. Inhibition of ROCK significantly reduced blood pressure in human and animal models of hypertension, despite the precise molecular mechanism underling the anti-hypertensive effect not being fully understood.

Thus, we hypothesize that ROCK participates in the regulation of aortic stiffness via altering VSMC stiffness in hypertension. In this study, we integrated atomic force microscopy (AFM) and molecular approaches to determine whether increased stiffness of aortic VSMCs in hypertensive rats is ROCK-dependent, and whether the anti-hypertensive effect of ROCK inhibitors contributes to the reduction of aortic stiffness via changing VSMC mechanical properties.

Despite a widely held belief that aortic stiffening is associated with changes in extracellular matrix proteins and endothelial dysfunction, our recent studies demonstrated that intrinsic stiffening of aortic VSMCs, independent of VSMC proliferation and migration, is an important contributor to aortic wall stiffening both in hypertensive and aged animals. The present study demonstrates for the first time that ROCK is a novel mediator of aortic VSMC stiffening in hypertension, which has never been described previously. Furthermore, our study also indicated that attenuation of aortic VSMC stiffening by pharmacological inhibition can serve as a promising therapeutic target to correct aortic stiffening not only in hypertension, but also in other age-related vascular diseases.


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