Published Online
on June 17, 2002

A more recent version of this article appeared on July 16, 2002

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Submitted on February 28, 2002
Revised on May 1, 2002
Accepted on May 1, 2002

ß₂-Adrenergic Receptor Gene Delivery to the Endothelium Corrects Impaired Adrenergic Vasorelaxation in Hypertension

Guido Iaccarino MD, PhD^*, Ersilia Cipolletta MD, Antonia Fiorillo MD, Mario Annecchiarico MD, Michele Ciccarelli MD, Vincenzo Cimini PhD, Walter J. Koch PhD, and Bruno Trimarco MD

From the Department of Clinical Medicine, Cardiovascular and Immunological Sciences (G.I., E.C., A.F., M.A., M.C., B.T.), and Biomorphological and Functional Sciences (V.C.), Federico II University, Naples, Italy; and the Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC.

^* To whom correspondence should be addressed. E-mail: guiaccar{at}unina.it.

Background—Impaired ß-adrenergic receptor (AR)--mediated vasorelaxation in hypertension plays a role in increased peripheral vascular resistance and blood pressure. Because the ß₂AR is the most abundant vascular AR subtype, we sought to enhance ßAR vasorelaxation by overexpressing ß₂ARs via adenoviral-mediated gene transfer (ADß₂AR) 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 ADß₂AR 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 ß₂AR overexpression (2-fold) was studied in isolated organ baths. ADß₂AR carotid responses to ₁AR and ₂AR agonists were not affected, whereas responses to epinephrine were altered and ßAR-mediated vasorelaxation was enhanced after ß₂AR overexpression. As expected, ßAR-mediated vasodilatation in control carotids of SHR rats was significantly less than in similar control WKY carotid arteries. ADß₂AR treatment enhanced ßAR vasorelaxation in SHR to levels similar to those seen in ADß₂AR WKY carotids.

Conclusions—Our results demonstrate a critical role for the endothelium in ßAR-mediated vasorelaxation and suggest that impaired ßAR signaling may account for dysfunctional ßAR vasorelaxation in hypertension rather than impaired endothelium-dependent nitric oxide metabolism.

Key words: endothelium • gene therapy • hypertension • signal transduction

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