Gene transfer of calcitonin gene-related peptide to cerebral arteries

Overexpression of calcitonin gene-related peptide (CGRP), an extremely pote nt vasodilator, to blood vessels is a possible strategy for prevention of v asospasm. We constructed an adenoviral vector that encodes prepro-CGRP (Adp repro-CGRP) and examined the effects of gene transfer on cultured cells and cerebral arteries. Transfection of Adprepro-CGRP to Cos-7 and NIH-3T3 cell s increased CGRP-like immunoreactivity in media and produced an increase in cAMP in recipient cells. Five days after injection of Adprepro-CGRP into t he cisterna magna of rabbits, the concentration of CGRP-like immunoreactivi ty increased by 93-fold in cerebrospinal fluid. In basilar artery, cAMP inc reased by 2.3-fold after Adprepro-CGRP compared with a control adenovirus. After transfection of Adprepro-CGRP, contraction of basilar artery in vitro to histamine and serotonin was attenuated, and relaxation to an inhibitor of cyclic nucleotide phosphodiesterase 3-isobutyl-1-methylxanthine was augm ented compared with nontransduced arteries or arteries transfected with a c ontrol gene. Altered vascular responses were restored to normal by pretreat ment with a CGRP(1) receptor antagonist CGRP-(8-37). Thus gene transfer of prepro-CGRP in vivo overexpresses CGRP in cerebrospinal fluid and perivascu lar tissues and modulates vascular tone. We speculate that this approach ma y be useful in prevention of vasospasm after subarachnoid hemorrhage.