Deletion of T-type calcium channels Ca_v3.1 or Ca_v3.2 attenuates endothelial dysfunction in aging mice

Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Ca_v3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function was determined in mesenteric arteries (perfusion) and aortae (isometric contraction) of young and old wild-type (WT), Ca_v3.1, and Ca_v3.2 knockout mice. NO production was measured by fluorescence imaging in mesenteric arteries. With age, endothelium-dependent subsequent dilatation (following depolarization with KCl) of mesenteric arteries was diminished in the arteries of WT mice, unchanged in Ca_v3.2^-/- preparations but increased in those of Ca_v3.1^-/- mice. NO synthase inhibition abolished the subsequent dilatation in mesenteric arteries and acetylcholine-induced relaxations in aortae. NO levels were significantly reduced in mesenteric arteries of old compared to young WT mice. In Ca_v3.1^-/- and Ca_v3.2^-/- preparations, NO levels increased significantly with age. Relaxations to acetylcholine were significantly smaller in the aortae of old compared to young WT mice, while such responses were comparable in preparations of young and old Ca_v3.1^-/- and Ca_v3.2^-/- mice. The expression of Ca_v3.1 was significantly reduced in aortae from aged compared to young WT mice. The level of phosphorylated eNOS was significantly increased in aortae from aged Ca_v3.1^-/- mice. In conclusion, T-type calcium channel-deficient mice develop less age-dependent endothelial dysfunction. Changes in NO levels are involved in this phenomenon in WT and Ca_v3.1^-/- mice. These findings suggest that T-type channels play an important role in age-induced endothelial dysfunction.