Age-dependent impact of CaV3.2 T-type calcium channel deletion on myogenic tone and flow-mediated vasodilatation in small arteries

The myogenic response and flow-mediated vasodilatation are important regulators of local blood perfusion and total peripheral resistance, and are known to entail a calcium influx into vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), respectively. Ca(V)3.2 T-type calcium channels are expressed in both VSMCs and ECs of small arteries. The T-type channels are important drug targets but, as a result of the lack of specific antagonists, our understanding of the role of Ca(V)3.2 channels in vasomotor tone at various ages is scarce. We evaluated the myogenic response, flow-mediated vasodilatation, structural remodelling and mRNA + protein expression in small mesenteric arteries from Ca(V)3.2 knockout (Ca(V)3.2KO) vs. wild-type mice at a young vs. mature adult age. In young mice only, deletion of Ca(V)3.2 led to an enhanced myogenic response and a similar to 50% reduction of flow-mediated vasodilatation. Ni2+ had both Ca(V)3.2-dependent and independent effects. No changes in mRNA expression of several important K+ and Ca2+ channel genes were induced by Ca(V)3.2KO However, the expression of the other T-type channel isoform (Ca(V)3.1) was reduced at them RNA and protein level in mature adult compared to young wild-type arteries. The results of the present study demonstrate the important roles of the Ca(V)3.2 T-type calcium channels inmyogenic tone and flow-mediated vasodilatation that disappear with ageing. Because increased arterial tone is a risk factor for cardiovascular disease, we conclude that Ca(V)3.2 channels, by modulating pressure-and flow-mediated vasomotor responses to prevent excess arterial tone, protect against cardiovascular disease.