PHYSIOLOGICAL REGUALTION OF CEREBRAL CIRCULATION--GENE TRANSFER OF NITRIC OXIDE S

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Gene transfer approaches are a novel, potentially valuable method to study vascular biology. Gene transfer to cerebral blood vessels, however, is extremely difficult. The investigators have described the first gene transfer to intracranial blood vessels and perivascular tissue in vivo, which was accomplished by injection of a replication-deficient adenovirla vector into cerebrospinal fluid. The investigators have used adenovirus that expresses beta- galactosidase, the product of a reporter gene. A major next step will be alteration of function of intracranial blood vessels by gene transfer. The goal of this project is to alter vasomotor function of the carotid artery and intracranial vessels by gene transfer of endothelial nitric oxide synthase (eNOS) in normal animals and eNOS knockout mice. The investigators have cloned the gene for eNOS into an adenoviral vector. Before attempting to alter vasomotor function in cerebral blood vessels in vivo, the investigators will attempt to augment eNOS-mediated vasodilatation by gene transfer to the carotid artery in vitro. Preliminary studies suggest that this approach is feasible. The critical next step in development of gene transfer approaches to the cerebral circulation is to alter vascular function of cerebral blood vessels in vivo. Studies are proposed to determine whether gene transfer of eNOS to cerebral vessels in vivo produces augmented vasodilatation of NO-mediated stimuli in the carotid artery, intracranial cerebral arterioles, and the basilar artery. Detection of improvement of NO-mediated responses by gene transfer of eNOS may be facilitated in eNOS knockout mice. Studies are planned in eNOS knockout mice to determine whether gene transfer of eNOS to the aorta and carotid artery restores NO- mediated responses and whether gene transfer of eNOS to intracranial blood vessels in vivo in eNOS knockout mice reduces the role of compensatory mechanisms. The purpose of these studies is two-fold: to develop methods for gene transfer to cerebral vessels, and to use these approaches as a tool to study vascular biology.