Age-dependent impact of Ca 3.2 T-type calcium channel deletion on myogenic tone and flow-mediated vasodilatation in small arteries.

KEY POINTS

Blood pressure and flow exert mechanical forces on the walls of small arteries, which are detected by the endothelial and smooth muscle cells, and lead to regulation of the diameter (basal tone) of an artery. Ca 3.2 T-type calcium channels are expressed in the wall of small arteries, although their function remains poorly understood because of the low specificity of T-type blockers. We used mice deficient in Ca 3.2 channels to study their role in pressure- and flow-dependent tone regulation and the possible impact of ageing on this role. In young mice, Ca 3.2 channels oppose pressure-induced vasoconstriction and participate in endothelium-dependent, flow-mediated dilatation. These effects were not seen in mature adult mice. The results of the present study demonstrate an age-dependent impact of Ca 3.2 T-type calcium channel deletion in rodents and suggest that the loss of Ca 3.2 channel function leads to more constricted arteries, which is a risk factor for cardiovascular disease.

ABSTRACT

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 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 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 3.2 knockout (Ca 3.2KO) vs. wild-type mice at a young vs. mature adult age. In young mice only, deletion of Ca 3.2 led to an enhanced myogenic response and a ∼50% reduction of flow-mediated vasodilatation. Ni had both Ca 3.2-dependent and independent effects. No changes in mRNA expression of several important K and Ca channel genes were induced by Ca 3.2KO However, the expression of the other T-type channel isoform (Ca 3.1) was reduced at the mRNA 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 3.2 T-type calcium channels in myogenic tone and flow-mediated vasodilatation that disappear with ageing. Because increased arterial tone is a risk factor for cardiovascular disease, we conclude that Ca 3.2 channels, by modulating pressure- and flow-mediated vasomotor responses to prevent excess arterial tone, protect against cardiovascular disease.