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

Abstract

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 (8×10 8 pfu), AdRSVβgal (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 AdRSVβgal 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 AdRSVβgal ( P <0.005). In rabbits treated with vehicle or AdRSVβgal, 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 CGRP 1 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.