Aortic and Carotid Arterial Stiffness and Epigenetic Regulator Gene Expression Changes Precede Blood Pressure Rise in Stroke-Prone Dahl Salt-Sensitive Hypertensive Rats

Abstract

Multiple clinical studies show that arterial stiffness, measured as pulse wave velocity (PWV), precedes hypertension and is an independent predictor of hypertension end organ diseases including stroke, cardiovascular disease and chronic kidney disease. Risk factor studies for arterial stiffness implicate age, hypertension and sodium. However, causal mechanisms linking risk factor to arterial stiffness remain to be elucidated. Here, we studied the causal relationship of arterial stiffness and hypertension in the Na-induced, stroke-prone Dahl salt-sensitive (S) hypertensive rat model, and analyzed putative molecular mechanisms. Stroke-prone and non-stroke-prone male and female rats were studied at 3- and 6-weeks of age for arterial stiffness (PWV, strain), blood pressure, vessel wall histology, and gene expression changes. Studies showed that increased left carotid and aortic arterial stiffness preceded hypertension, pulse pressure widening, and structural wall changes at the 6-week time-point. Instead, differential gene induction was detected implicating molecular-functional changes in extracellular matrix (ECM) structural constituents, modifiers, cell adhesion, and matricellular proteins, as well as in endothelial function, apoptosis balance, and epigenetic regulators. Immunostaining testing histone modifiers Ep300, HDAC3, and PRMT5 levels confirmed carotid artery-upregulation in all three layers: endothelial, smooth muscle and adventitial cells. Our study recapitulates observations in humans that given salt-sensitivity, increased Na-intake induced arterial stiffness before hypertension, increased pulse pressure, and structural vessel wall changes. Differential gene expression changes associated with arterial stiffness suggest a molecular mechanism linking sodium to full-vessel wall response affecting gene-networks involved in vascular ECM structure-function, apoptosis balance, and epigenetic regulation.

The Conundrum of Arterial Stiffness, Elevated Blood Pressure, and Aging

“…Similarly Dahl salt-sensitive hypertensive rats develop an increase in PWV that precedes the increase in blood pressure in response to salt loading 24 . Although these experimental animal models did not address the issue of aging, however, in reality, they do support the notion that the increase in PWV occurs independent of pressure changes.…”

Building on a Legacy of Hypertension Research

“…A recent example of the virtuous circle connecting experimental and real world recent findings in hypertension was offered by the concurrence of not only the results but also the timing of findings obtained from basic and epidemiological research studies funded by the NHLBI in an effort to clarify the relationship between arterial stiffening and hypertension. Several concurrent basic research studies confirmed that arterial stiffening preceded overt hypertension in different experimental models, including the elastin-deficient mice 16 , obese mice 17 , or stroke-prone Dahl salt-sensitive hypertensive rats 18 . The same temporal sequence, i.e.…”

A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension

“…7 At this age, both stroke-prone and non-stroke-prone rats had similar blood pressure. However, at 16 weeks of age, stroke-prone Dahl-S rats started to show significantly higher blood pressure than non-stroke-prone Dahl-S rats, again consistent with the conclusion that arterial stiffness precedes hypertension.…”