Received for publication June 19, 2006.
Revised July 17, 2006.
Accepted for publication August 2, 2006.

Adenylyl Cyclase 6 Over-Expression Decreases The Permeability Of Endothelial Monolayers Via Preferential Enhancement Of Prostacyclin Receptor Function

Abstract

Over-expression of adenylyl cyclase (AC) has been proposed as a potential gene therapy strategy to increase cAMP formation in cardiomyocytes and cardiac function in vivo. The impact of AC over-expression on endothelial cells, which will be traversed by genes delivered in vivo, has not been examined. Hence, the goal of the current study was to determine the consequence of AC over-expression on vascular endothelial cells, in terms of G-protein coupled receptor (GPCR) signaling and endothelial barrier function. We demonstrate that adenoviral-mediated gene transfer of AC6 in human umbilical vein endothelial cells (HUVEC) preferentially enhances prostacyclin receptor (vs. other GPCR)-stimulated cAMP synthesis and, in parallel, inhibits thrombin-stimulated increases in endothelial cell barrier function. Using multiple strategies, including prostacyclin receptor-targeted siRNA, we identify that the enhancement of endothelial barrier function by AC6 over-expression is dependent on an autocrine/paracrine feedback pathway involving release of prostacyclin and activation of prostacyclin receptors. AC6 over-expression in endothelial cells may have utility as a means to enhance prostacyclin function and reduce endothelial barrier permeability.

Key words: Prostanoid, Thrombin/PAR, Adenylyl cyclases, cAMP, Overexpression

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