title: 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 (2M) and 12-month-old (12M) 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 2M decreased from 44% to 21%. MAX to ISO in vessels from 12M decreased from 12% to 6%. Sensitivity (ED₅₀) in vessels from 2M and 12M 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 2M increased from 44% to 58%. MAX in vessels from 12M increased from 15% to 69%. ED₅₀ in vessels from 2M and 12M 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.
authors.affiliation: Portland VA Medical Center, Research Service, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, United States.
authors.forename: William E
authors.initials: WE
authors.lastname: Schutzer
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
authors.forename: John
authors.initials: J
authors.lastname: Reed
authors.forename: Terry
authors.initials: T
authors.lastname: Oyama
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Beard
authors.forename: Sharon
authors.initials: S
authors.lastname: Anderson
authors.forename: Scott L
authors.initials: SL
authors.lastname: Mader
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2