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

William E. Schutzer, Hong Xue, John Reed, Terry Oyama, Douglas R. Beard, Sharon Anderson, Scott L. Mader

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)178-188
Number of pages11
JournalVascular Pharmacology
Volume55
Issue number5-6
DOIs
StatePublished - Nov 1 2011

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Keywords

  • Adenovirus
  • Adrenergic-beta
  • Aging
  • Fischer 344
  • G protein receptor kinase (GRK)
  • Vasorelaxation

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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