Viral‐Mediated Gene Delivery Of Constitutively Activated GΑS Alters Vasoreactivity

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Abstract
SUMMARY: 1. Decline in β‐adrenoceptor (β‐AR)‐mediated function occurs with increasing age, as well as in multiple disease conditions. The mechanisms responsible for this decline include alterations in β‐AR itself, β‐AR coupling proteins, such as G‐proteins, or other β‐AR‐linked proteins, such as G‐protein receptor kinases and/or phosphatases.2. The present study examines the physiological effects of in vitro transfer of constitutively activated Gαs (Gαs‐Q227L) to both cultured vascular smooth muscle cells (VSMC) and whole aortic tissue of 6‐month‐old (adult) animals via a replication‐deficient Herpes simplex virus (HSV) vector. These studies were conducted to provide a model for future examination of the role of Gαs in the age‐related decline in β‐AR‐mediated vasorelaxation.3. Gene transfer was confirmed by western blotting for specific proteins. Aortic tissue infected with HSV–Gαs‐Q227L had reduced phenylephrine‐induced contraction and enhanced isoproterenol‐stimulated vasorelaxation. Infection of cultured VSMC with HSV–Gαs‐Q227L increased both basal‐ and isoproterenol‐stimulated cAMP accumulation, whereas forskolin‐stimulated cAMP production was unchanged.4. These results implicate Gαs as a target for further investigation in age‐related changes in vascular reactivity and support the use of viral‐mediated gene transfer as an effective tool to study adrenergic signal transduction and physiology in vascular tissue.