Intracellular pH in the Resistance Vasculature: Regulation and Functional Implications

Abstract

Net acid extrusion from vascular smooth muscle (VSMCs) and endothelial cells (ECs) in the wall of resistance arteries is mediated by the Na⁺,HCO₃^– cotransporter NBCn1 ( SLC4A7) and the Na⁺/H⁺ exchanger NHE1 ( SLC9A1) and is essential for intracellular pH (pH_i) control. Experimental evidence suggests that the pH_i of VSMCs and ECs modulates both vasocontractile and vasodilatory functions in resistance arteries with implications for blood pressure regulation. The connection between disturbed pH_i and altered cardiovascular function has been substantiated by a genome-wide association study showing a link between NBCn1 and human hypertension. On this basis, we here review the current evidence regarding (a) molecular mechanisms involved in pH_i control in VSMCs and ECs of resistance arteries at rest and during contractions, (b) implications of disturbed pH_i for resistance artery function, and (c) involvement of disturbed pH_i in the pathogenesis of vascular disease. The current evidence clearly implies that pH_i of VSMCs and ECs modulates vascular function and suggests that disturbed pH_i either consequent to disturbed regulation or due to metabolic challenges needs to be taken into consideration as a mechanistic component of artery dysfunction and disturbed blood pressure regulation.