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

Jonathon M. Willets,Richard D. Rainbow,R. A. John Challiss,Carl P. Nelson,Craig A. Nash

doi:10.1152/ajpcell.00079.2015

Jonathon M. Willets, Richard D. Rainbow + Show 3 more

Open Access

https://doi.org/10.1152/ajpcell.00079.2015

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Abstract

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 signaling 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 signaling and function. Arrestin2/3 expression was increased in mesenteric arteries of 12-wk-old spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) controls, while no differences in arrestin expression were observed between 6-wk-old SHR and WKY animals. In mesenteric artery myography experiments, high extracellular K+-stimulated contractions were increased in both 6- and 12-wk-old SHR animals. Concentration-response experiments for uridine 5′-triphosphate (UTP) acting through P2Y receptors displayed a leftward shift in 12-wk, but not 6-wk-old animals. Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals. Dual IP3/Ca2+ imaging in mesenteric arterial cells showed that desensitization of UTP and endothelin-1 (ET1) responses was enhanced in 12-wk-old (but not 6-wk-old) SHR compared with WKY rats. siRNA-mediated depletion of arrestin2 for UTP and arrestin3 for ET1, reversed the desensitization of PLC signaling. 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 signaling and vessel contraction. Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.

Highlights

HYPERTENSION IS AN IMPORTANT risk factor in the development of major cardiac, cerebral, and renal diseases
Analysis of protein expression in the resistance arteries of the mesenteric tree of 6-wk-old animals showed there were no significant differences in arrestin expression in the vessels of spontaneously hypertensive rats (SHR) and WKY at this age (Fig. 1, A and B)
In contrast to our findings in 6-wk-old animals, arrestin2 expression was significantly increased in both mesenteric vessels and aortae of 12-wk-old SHR compared with WKY rats (Fig. 1, A–D), with the highest expression being observed in SHR mesentery

Summary

Introduction

HYPERTENSION IS AN IMPORTANT risk factor in the development of major cardiac, cerebral, and renal diseases. GRK and arrestin proteins are important negative regulators of contractile signaling, and it might be expected that their expression increases in hypertension to counteract vasoconstrictor-stimulated vessel contraction. This is the case; despite the fact that arterial smooth muscle cells express multiple isoenzymes of the GRK family [22], only GRK2 expression has been reported to be elevated in both hypertensive patients [8] and in rodent models of hypertension [9, 10].

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