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.
Highlights
Multiple studies of arterial stiffness in humans, typically measured as carotid-femoral pulse wave velocity and referred to as aortic stiffness, have demonstrated that arterial stiffness is an independent risk factor for cardiovascular outcomes in hypertensive patients including mortality [1], myocardial infarction [2], fatal stroke in essential hypertension [3], and cerebral microbleeds which predict cerebral hemorrhage [4]
Addressing whether arterial stiffness precedes vascular diseases or is secondary to it, association studies in humans reported that arterial stiffness was an independent predictor of progression to hypertension in non-hypertensive subjects [9], and that increased aortic stiffness, decreased aortic strain and decreased aortic distensibility have been observed in both hypertensive patients and young patients with prehypertension [10]
To gain insight into causal mechanisms of arterial stiffness, we evaluated the structural and molecular changes in the blood vessels exhibiting increased stiffness measured as pulse wave velocity (PWV), and studied both the carotid artery and aorta
Summary
Multiple studies of arterial stiffness in humans, typically measured as carotid-femoral pulse wave velocity (cfPWV) and referred to as aortic stiffness, have demonstrated that arterial stiffness is an independent risk factor for cardiovascular outcomes in hypertensive patients including mortality [1], myocardial infarction [2], fatal stroke in essential hypertension [3], and cerebral microbleeds which predict cerebral hemorrhage [4]. A 2time point prospective study in the Framingham Offspring cohort observed that aortic stiffness, brachial pulse pressure, peripheral wave reflection, and central pressure pulsatility; along with macroand micro-vascular endothelial function jointly preceded essential hypertension [11] These multiple studies showed that arterial stiffness preceded hypertension and predicts its target organ complications independent of other risk factors studied (diabetes, smoking, cholesterol levels, and waist circumference). These studies did not report concurrent analysis of sodium intake as risk factor, other studies in different populations, China [12], Australia [13] and Europe [14], have shown association between dietary sodium and arterial stiffness independent of blood pressure and measurement modalities [15,16,17]. This paradigm is concordant with aging-associated arterial stiffness [18], aging-associated salt-sensitivity [19,20] and the observation of increased hypertension with aging [21,22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
