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(Circulation Research. 2000;87:818.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Gene Transfer of Calcitonin Gene–Related Peptide Prevents Vasoconstriction After Subarachnoid Hemorrhage

Kazunori Toyoda, Frank M. Faraci, Yoshimasa Watanabe, Toshihiro Ueda, Jon J. Andresen, Yi Chu, Shoichiro Otake, Donald D. Heistad
Abstract—We sought to determine whether adenovirus-mediated gene transfer in vivo of calcitonin gene–related peptide (CGRP), a potent vasodilator, ameliorates cerebral vasoconstriction after experimental subarachnoid hemorrhage (SAH). Arterial blood was injected into the cisterna magna of rabbits to mimic SAH 5 days after injection of AdRSVCGRP (8x10⁸ pfu), AdRSVßgal (control virus), or vehicle. After injection of AdRSVCGRP, there was a 400-fold increase in CGRP in cerebrospinal fluid. Contraction of the basilar artery to serotonin in vitro was greater in rabbits after SAH than after injection of artificial cerebrospinal fluid (P<0.001). Contraction to serotonin was less in rabbits with SAH after AdRSVCGRP than after AdRSVßgal or vehicle (P<0.02). Basal diameter of the basilar artery before SAH (measured with digital subtraction angiogram) was 13% greater in rabbits treated with AdRSVCGRP than in rabbits treated with vehicle or AdRSVßgal (P<0.005). In rabbits treated with vehicle or AdRSVßgal, arterial diameter after SAH was 25±3% smaller than before SAH (P<0.0005). In rabbits treated with AdRSVCGRP, arterial diameter was similar before and after SAH and was reduced by 19±3% (P<0.01) after intracisternal injection of CGRP-(8-37) (0.5 nmol/kg), a CGRP₁ receptor antagonist. To determine whether gene transfer of CGRP after SAH may prevent cerebral vasoconstriction, we constructed a virus with a cytomegalovirus (CMV) promoter, which results in rapid expression of the transgene product. Treatment of rabbits with AdCMVCGRP after experimental SAH prevented constriction of the basilar artery 2 days after SAH. Thus, gene transfer of CGRP prevents cerebral vasoconstriction in vivo after experimental SAH.

Key Words: gene therapy • cerebral vasospasm • vasodilation • neuropeptide • rabbit

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