Defining the roles of arrestin2 and arrestin3 in vasoconstrictor receptor desensitization in hypertension

Prolonged vasoconstrictor-stimulated phospholipase C activity can induce arterial constriction, hypertension and smooth muscle hypertrophy/hyperplasia. Arrestin proteins are recruited by agonist-occupied G protein-coupled receptors to terminate signalling and counteract changes in vascular tone. Here we determine whether the development of hypertension affects arrestin expression in resistance arteries, and how such changes alter arterial contractile signalling and function. Arrestin2/3 expression was increased in mesenteric arteries of 12 week-old spontaneously-hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) controls, while no differences in arrestin expression were observed between 6 week-old SHR and WKY animals. In mesenteric artery myography experiments, high extracellular K[superscript: +]-stimulated contractions were increased in both 6 and 12 week-old SHR animals. Concentration-response experiments for uridine 5'-triphosphate (UTP) acting through P2Y receptors displayed a leftward shift in 12 week, but not 6 week-old animals. Desensitization of UTP-stimulated vessel contractions was increased in 12 (but not 6) week-old SHR animals. Dual IP[subscript: 3]/Ca[superscript: 2+] imaging in mesenteric arterial cells showed that desensitization of UTP and endothelin-1 (ET1) responses, was enhanced in 12 (but not 6) week-old SHR compared to WKY rats. siRNA-mediated depletion of arrestin2 for UTP and arrestin3 for ET1, reversed the desensitization of PLC signalling. In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signalling and vessel contraction. Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.