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[alpha]-Calcitonin gene-related peptide ([alpha]CGRP) is a vasodilator, but there is limited knowledge of its long-term cardiovascular protective influence. We hypothesized that [alpha]CGRP protects against the onset and development of angiotensin II-induced hypertension and have identified protective mechanisms at the vascular level. Wild-type and [alpha]CGRP knockout mice that have similar baseline blood pressure were investigated in the angiotensin II hypertension model for 14 and 28 days. [alpha]CGRP knockout mice exhibited enhanced hypertension and aortic hypertrophy. [alpha]CGRP gene expression was increased in dorsal root ganglia and at the conduit and resistance vessel level of wild-type mice at both time points. [beta]CGRP gene expression was also observed and shown to be linked to plasma levels of CGRP. Mesenteric artery contractile and relaxant responses in vitro and endothelial NO synthase expression were similar in all groups. The aorta exhibited vascular hypertrophy, increased collagen formation, and oxidant stress markers in response to angiotensin II, with highest effects observed in [alpha]CGRP knockout mice. Gene and protein expression of endothelial NO synthase was lacking in the aortae after angiotensin II treatment, especially in [alpha]CGRP knockout mice. These results demonstrate the ongoing upregulation of [alpha]CGRP at the levels of both conduit and resistance vessels in vascular tissue in a model of hypertension and the direct association of this with protection against aortic vascular hypertrophy and fibrosis. This upregulation is maintained at a time when expression of aortic endothelial NO synthase and antioxidant defense genes have subsided, in keeping with the concept that the protective influence of [alpha]CGRP in hypertension may have been previously underestimated.

(C) 2014 American Heart Association, Inc