β 2 -Adrenergic Receptor Gene Delivery to the Endothelium Corrects Impaired Adrenergic Vasorelaxation in Hypertension

Abstract

Background — Impaired β-adrenergic receptor (AR)–mediated vasorelaxation in hypertension plays a role in increased peripheral vascular resistance and blood pressure. Because the β 2 AR is the most abundant vascular AR subtype, we sought to enhance βAR vasorelaxation by overexpressing β 2 ARs via adenoviral-mediated gene transfer (ADβ 2 AR) to the vascular endothelium of the carotid artery. Methods and Results — In normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, we exposed the right common carotid artery to ADβ 2 AR in situ for 15 minutes by injection into the lumen while the blood flow was interrupted. Control carotids received an empty vector (ADempty). Three days later, transgene expression and selective endothelial localization were confirmed in infected vessels. Vasoregulation after β 2 AR overexpression (2-fold) was studied in isolated organ baths. ADβ 2 AR carotid responses to α 1 AR and α 2 AR agonists were not affected, whereas responses to epinephrine were altered and βAR-mediated vasorelaxation was enhanced after β 2 AR overexpression. As expected, βAR-mediated vasodilatation in control carotids of SHR rats was significantly less than in similar control WKY carotid arteries. ADβ 2 AR treatment enhanced βAR vasorelaxation in SHR to levels similar to those seen in ADβ 2 AR WKY carotids. Conclusions — Our results demonstrate a critical role for the endothelium in βAR-mediated vasorelaxation and suggest that impaired βAR signaling may account for dysfunctional βAR vasorelaxation in hypertension rather than impaired endothelium-dependent nitric oxide metabolism.