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.

Intracellular Acidification Alters Myogenic Responsiveness and Vasomotion of Mouse Middle Cerebral Arteries

“…2 Intracellular pH Regulation Regulation of pH i in VSMCs is largely Na þ dependent and is mediated by Na þ /H þ exchange and Na þ ,HCO 3 À cotransport. 19 To determine the contribution of NBCn1 to Na þ ,HCO 3 À cotransport in the middle cerebral arteries, we measured the rate of amiloride-insensitive, Na þ -dependent pH i recovery from intracellular acidification (Figures 1A and 1B). An original trace is shown in Supplementary Figure 1.…”

Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation

“…It is well known that pHi is regulated within narrow limits in animal cells (approx. 7.4) and generally an increase in pHi has been correlated with an increase in cell activity, whereas the pHi is reduced during cellular quiescence and decreased cell activity (Boedtkjer and Aalkjaer, 2012;Gottlieb et al, 1996;McQueen and Bailey, 1991;Meisenholder et al, 1996). We confirmed previous reports showing that various celldamaging agents could evoke cellular acidification which could be a step in the execution of necrotic and/or apoptotic cell death (Ding et al, 2000;Lagadic-Gossmann et al, 2004;Matsuyama et al, 2000;Vincent et al, 1999b).…”

pH sensing and regulation in cancer

“…It has been shown via functional assays that the Na + /HCO − 3 co-transporter (NBCn1) is the predominant mechanism for acid extrusion in breast carcinoma tissue when pH i levels are greater than 6.6 (Boedtkjer et al, 2013). In fact, inhibition of NBCn1, in NHE1 expressing cells, resulted in pH i acidification suggesting that NBCn1 should garner further attention as a therapeutic target (Boedtkjer and Aalkjaer, 2012; Boedtkjer et al, 2012). …”