Activation of voltage-gated Na+ channels induces vasorelaxation of murine mesenteric arteries, unmasking a cross-talk between Nav channels, NCX exchangers and eNO-synthase

Abstract

Blood vessel cells express voltage-gated Na+ channels (Nav channels) and their activation induces a Ca2+ response mediated by Na ± Ca2 + exchangers (NCX) in Ca2+ entry mode. Nevertheless, the physiological role of Nav channels in vascular tissue is still controversial. Our study aims to identify the Nav channel subtypes in resistance arteries and to define their contribution to the regulation of their vasomotricity by physiological and pharmacological approaches. To this end, we used mesenteric arteries (MA), as a suitable model of resistance artery from 5-month-old mice (C57Bl6/J, male and female). Our RT-qPCR results showed the expression of three transcripts encoding Nav1.2 (scn2a), Nav1.3 (scn3a) and Nav1.5 (scn5a) in MA from male and female mice. The presence of Nav channels in these arteries were confirmed by histoimmunostaining. Interestingly, wire myography results showed that the Nav channel activation by veratridine (VTD) induced the vasorelaxation of MA. Since the VTD-induced vasorelaxation was totally abolished by eNO-synthase inhibitor (L-NNA), it reveals that the Nav channel activation can stimulate eNO-synthase (eNOS). Thereafter, we investigated the involvement of NCX in these effects. We established the gene expression profile of NCX in murine MA by RT-qPCR, revealing the detection of slc8a1 (NCX1) and slc8a2 (NCX2). We observed that VTD-induced vasorelaxation was strongly decreased by NCX inhibition. Altogether, our data highlight for the first time the role of Nav channels in vasorelaxation response in murine MA. The activation of Nav channels induces Na+ entry and subsequent membrane depolarization, which trigger Ca2+ entry through NCX. This possible Nav channels-NCX cross-talk might be an important feature of the link between Na+ and Ca2+ homeostasis in vascular cells.