Recombinant nitric oxide synthase gene transfer: Potential roles in gene therapy of cerebrovascular disease

Gene therapy refers to the transfer of functional genes to the host tissue to correct the malfunction of a specific gene or to replace a missing gene, with resultant alleviation of the symptoms of a particular disease. Cerebrovascular gene transfer is not only a powerful technique for studying cerebrovascular biology, it is a novel and promising strategy for treating intracranial vascular disorders. Nitric oxide (NO) exerts critical and diverse functions in cerebral circulation. Impaired NO production or function contributes to the pathophysiology of cerebrovascular diseases, such as subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. Although NO therapy is desirable, the short half-life of NO and the tolerance and side effects of NO donors often impede their clinical applications. We have recently constructed replication-incompetent adenoviral vectors encoding the endothelial NO synthase (eNOS) gene and conducted both ex vivo and in vivo gene transfer studies to cerebral arteries. Our results indicate that transgene and recombinant eNOS protein can be effectively expressed in endothelium and adventitia of cerebral vasculature, resulting in augmented relaxations in response to calcium ionophore and various agonists, with a concomitant increase in cyclic guanosine monophorphate (cGMP) formation. These findings suggest that cerebral arterial tone can be functionally modulated by recombinant eNOS expression following gene transfer, which may have important clinical implications for future treatment of cerebrovascular diseases including SAM-induced cerebral vasospasm.