Vasospasm is a common and devastating complication after subarachnoid hemorrhage (SAH), and a variety of therapeutic approaches have failed. Several lines of evidence indicate that calcitonin gene-related peptide (CGRP) is depleted from trigeminal sensory nerves after SAH, which implies that an important compensatory mechanism may be exhausted. In contrast to diminished responses to several other cerebral vasodilators, vasodilator responses to CGRP are preserved or enhanced after SAH. One goal of the studies that are proposed is to determine whether gene transfer in vitro can alter cerebral vascular function after SAH. The investigators have prepared recombinant adenoviral vectors that express endothelial nitric oxide synthase (eNOS) and prepro-CGRP. Studies are proposed to determine whether gene transfer in vitro of eNOS, inducible NOS (iNOS), and prepro-CGRP produces relaxation of intracranial arteries after SAH. The investigators will use a method that they have developed to study gene transfer to blood vessels in vitro. A second goal is to examine effects of SAH on transgene expression. The investigators have observed pronounced expression of beta galactosidase after gene transfer to dogs after SAH, using an adenoviral vector with a cytomegalovirus (CMV) promoter driving expression of beta galactosidase. Studies are proposed to determine whether transgene expression is increased by SAH when an adenoviral vector with a CMV, but not Rous sarcoma virus (RSV), promoter is used, perhaps because response elements in the CMV promoter are activated by NrkappaB translocated to the nucleus in response to oxidant stress. These experiments should clarify mechanisms that lead to augmented transgene expression after SAH. A third goal is to determine whether gene transfer of CGRP can alter cerebral vascular function and prevent vasospasm in vivo after SAH. Studies are proposed to determine whether gene transfer of eNOS, iNOS, and prepro-CGRP by injection of adenoviral vectors into cerebrospinal fluid inhibits development of vasospasm following SAH. The investigators plan to use a method that they have developed for gene transfer to cerebral vessels and perivascular tissue in vivo. Vascular responses will be examined in rat and canine models, and effects on vasospasm in canine model will be determined. Even with currently available vectors, which provide delayed and transient transfection, gene therapy to prevent vasospasm after SAH may be possible.
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