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

Abstract

Background-Impaired ␤-adrenergic receptor (AR)-mediated vasorelaxation in hypertension plays a role in increased peripheral vascular resistance and blood pressure. Because the ␤ 2 AR is the most abundant vascular AR subtype, we sought to enhance ␤AR vasorelaxation by overexpressing ␤ 2 ARs via adenoviral-mediated gene transfer (AD␤ 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 AD␤ 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 ␤ 2 AR overexpression (2-fold) was studied in isolated organ baths. AD␤ 2 AR carotid responses to ␣ 1 AR and ␣ 2 AR agonists were not affected, whereas responses to epinephrine were altered and ␤AR-mediated vasorelaxation was enhanced after ␤ 2 AR overexpression. As expected, ␤AR-mediated vasodilatation in control carotids of SHR rats was significantly less than in similar control WKY carotid arteries. AD␤ 2 AR treatment enhanced ␤AR vasorelaxation in SHR to levels similar to those seen in AD␤ 2 AR WKY carotids. Conclusions-Our results demonstrate a critical role for the endothelium in ␤AR-mediated vasorelaxation and suggest that impaired ␤AR signaling may account for dysfunctional ␤AR vasorelaxation in hypertension rather than impaired endothelium-dependent nitric oxide metabolism.

Exercise restores β-adrenergic vasorelaxation in aged rat carotid arteries

“…Our data suggest the importance of the integrity of vascular ␤-AR signaling for maintaining adequate levels of endothelial NO production and preserving the endothelial control of vascular tone. This observation is supported by the recent demonstration that the overexpression of ␤ 2 -ARs, via adenovirusmediated gene transfer to the vascular endothelium of the carotid artery, is able to correct impaired ␤-AR vasorelaxation in hypertensive rats (20).…”

“…Indeed, in rat carotids ␤-AR vasorelaxation is largely endothelium dependent (20). The physiological relevance of endothelial ␤-ARs is supported by their distribution in the vasculature.…”

“…Two endothelial cell lines from bovine aorta (BAEC; American Type Culture Collection) and aorta isolated from a 12-wk-old Wistar-Kyoto (WKY) rat as previously described (20) were assessed for ␤-ARK expression. Cells were cultured to 75% confluence in DMEM-10% FBS, washed twice in phosphatebuffered saline, and then Dounce homogenized with an insulin syringe in 25 mM Tris ⅐ HCl (pH 7.5), 5 mM EDTA, 5 mM EGTA, 10 g/ml leupeptin, 20 g/ml aprotinin, and 1 mM PMSF.…”

“…Right and left common carotid arteries were rapidly dissected free and cut into 4-mm-long rings. Vascular reactivity studies were conducted as previously described (20).…”

Long-Term Antioxidant Intervention Improves Myocardial Microvascular Function in Experimental Hypertension

“…Conversely, the attenuated response to dobutamine might result from HT-induced impairment in ␤-adrenoceptor-mediated vasodilation 40,41 or might reflect vascular remodeling. The greater improvement in the responses to adenosine than to dobutamine challenge in vitamin-treated HT might at least in part be related to their different mechanisms of action, because antioxidants are known to preferentially improve endothelium-dependent function.…”