Central Role of P2Y ₆ UDP Receptor in Arteriolar Myogenic Tone

Abstract

Objective Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT. Approach and Results We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X1 and P2Y6 was dominant. P2Y6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6−/− arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6−/− mice were protected against MT elevation in myocardial infarction–induced heart failure. Although both P2Y6 and P2Y2 receptors contributed to calcium mobilization, P2Y6 activation was mandatory for RhoA–GTP binding, myosin light chain, P42–P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43+/− and P2rx7−/− mesenteric resistance arteries. Conclusions Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.

Probenecid Inhibits α-Adrenergic Receptor–Mediated Vasoconstriction in the Human Leg Vasculature

“…These findings are in accordance with experiments performed in vitro and in gene modified animals demonstrating a coupling between Panx1 channels and α1-adrenoceptors 4–6 and suggest a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors in humans. The increase in heart rate probably represents a baroreflex-mediated effect to maintain MAP at a reduced total peripheral resistance, but direct cardiac effects cannot be excluded.…”

Endothelial cell Pannexin1 modulates severity of ischemic stroke by regulating cerebral inflammation and myogenic tone

“…However, deletion of SMC Panx1 did not alter the development of myogenic tone in cerebral arteries ( Figure 5, D and E). These data, coupled with the data above, suggest that EC Panx1 may regulate severity of cerebral ischemia/reperfusion injury Previous work has demonstrated that mesenteric arteries also utilize purinergic signaling to regulate myogenic tone, and Panx1 is expressed within the ECs of mesenteric arteries (11,26,27). In concordance with those experiments, we found that carbenoxolone treatment, which inhibits both Panx1 and Cx43 channels, significantly reduced myogenic tone development in third-order mesenteric arteries ( Figure 6, A-C), whereas spironolactone treatment, which does not inhibit Cx43 channels (25), did not impact mesenteric myogenic tone development ( Figure 6, D-F).…”

Role of age, Rho-kinase 2 expression, and G protein-mediated signaling in the myogenic response in mouse small mesenteric arteries

“…As a third aspect, Izzard and others discuss the issue that myogenic tone can protect vessels from vascular hypertrophy by lowering wall stress, which has been proposed to be the stimulus for hypertrophy (Izzard et al 2005). Recent studies have provided evidence that the G protein-coupled receptor (GPCR) mediated signaling is involved (Schnitzler et al 2008;Schleifenbaum et al 2014;Hui et al 2015;Storch et al 2015;Kauffenstein et al 2016) but mechano-activated ion channels (Welsh et al 2002;Drummond et al 2004;Earley et al 2004;Bulley et al 2012) and interactions between extracellular matrix proteins and membranespanning integrins (Martinez-Lemus et al 2003Jackson et al 2010;Colinas et al 2015) are also thought to contribute to the upstream sensing of pressure in the myogenic response. More detailed knowledge of the signaling pathways in the myogenic response is needed for a more complete understanding of the pathogenesis of hypertension and conditions that entail important risk factors for hypertension, such as: aging, abdominal obesity, diabetes, chronic mental stress, excess salt intake, high cholesterol, lack of physical exercise, or sleep apnea.…”