Age-related β-adrenergic receptor-mediated vasorelaxation is changed by altering G protein receptor kinase 2 expression

Abstract Beta-adrenergic receptor- (β-AR) mediated vasorelaxation declines with age. This change is likely related to receptor desensitization, rather than down regulation. One kinase responsible for desensitization is G protein receptor kinase 2 (GRK2). We have shown that GRK expression and activity increases with age in Fischer 344 rat aorta. In this study we validated that carotid arteries have similar age-related changes in the β-AR signaling axis as aorta. This finding allowed use of in vivo infection and delivery of two adenovirus vectors to carotid arteries of 2-month-old (2 M) and 12-month-old (12 M) male Fischer 344 rats. Adeno-GRK2 was used to overexpress GRK2, and adeno-β-ARK-ct was used to inhibit GRK2 function. Following a five-day infection, vessels were collected and ex vivo tissue bath was used to evaluate vasoreactivity. We used KCl contracted segments, and determined that overexpression of GRK2 significantly impaired isoproterenol (ISO)-mediated vasorelaxation in both age groups. Maximum relaxation (MAX) to ISO in vessels from 2 M decreased from 44% to 21%. MAX to ISO in vessels from 12 M decreased from 12% to 6%. Sensitivity (ED50 ) in vessels from 2 M and 12 M was also impaired 57%, and 30% respectively. We also determined that expression of adeno-β-ARK-ct significantly improved ISO-mediated vasorelaxation in both age groups. MAX in vessels from 2 M increased from 44% to 58%. MAX in vessels from 12 M increased from 15% to 69%. ED50 in vessels from 2 M and 12 M was also improved 46%, and 50% respectively. These findings further implicate age-related increases in GRK2 expression as an important regulator of the age-related decline in β-AR-mediated vasorelaxation.