Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl− cotransport-dependent signaling

Abstract

This study examines the action of agonists and antagonists of P2 receptors on mouse mesenteric artery contractions and the possible involvement of these signaling pathways in myogenic tone (MT) evoked by elevated intraluminal pressure. Both ATP and its non-hydrolyzed analog α,β-ATP triggered transient contractions that were sharply decreased in the presence of NF023, a potent antagonist of P2X 1 receptors. In contrast, UTP and UDP elicited sustained contractions which were suppressed by MRS2567, a selective antagonist of P2Y 6 receptors. Inhibition of Na + , K + , 2Cl − cotransport (NKCC) with bumetanide led to attenuation of contractions in UTP-but not ATPtreated arteries. Both UTP-induced contractions and MT were suppressed by MRS2567 and bumetanide but were insensitive to NF023. These data implicate a P2Y 6 -mediated, NKCC-dependent mechanism in MT of mesenteric arteries. The action of heightened intraluminal pressure on UTP release from mesenteric arteries and its role in the triggering of P2Y 6 -mediated signaling should be examined further.

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α 1 -Adrenergic Stimulation in Mice

“…25,26 WNK1 notably phosphorylates synaptotagmin 2, 25 modulating its plasma membrane binding and possibly affecting the release from or the insertion in the plasma membrane of several vesicle-associated proteins, such as ionic cotransporters, which, if not integrated correctly in the membrane, could possibly be targeted for degradation. Interestingly, NKCC1 has also been shown to regulate arterial BP 27,28 and to mediate ␣ 1 -adrenergic agonist-induced contractions in several models, 29,30 as well as myogenic response in mouse mesenteric arteries 31 and rat arterioles, 32 to the same extent as what we observed in Wnk1 ϩ/Ϫ mice. Taken together, this suggests that SPAK and NKCC1 could represent one of the signaling pathways involved downstream of L-WNK1 during Phe and myogenic vasoconstrictions.…”

Ageing alters perivascular nerve function of mouse mesenteric arteries in vivo

“…However, others have reported ≥20% myogenic tone in MA branches (Dubroca et al . 2007; Koltsova et al . 2009; Zhang et al .…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Contractile responses of the smooth muscle of the rat mesenteric artery were elicited by stimulation of P2Y 6 as well as P2X 1 receptors (Malmsjö et al, 2000a). Similarly, in mouse mesenteric arteries, there was evidence for contractile responses mediated by both P2Y 6 and P2X 1 receptors, because responses to UTP and UDP were reduced by a selective P2Y 6 antagonist, and a contractile response to a,b-meATP was blocked by the P2X 1 receptor antagonist NF023 (Koltsova et al, 2009). G proteincoupled receptor kinase 2 and arrestin-2 regulate UTPstimulated P2Y 2 receptors mediating constriction of rat mesenteric artery smooth muscle (Morris et al, 2011).…”

“…The dominance of P2X 1 receptors in mediating currents in smooth muscle cells of the rat mesenteric artery was confirmed, and no evidence for an involvement of P2X 4 , P2X 5 , or P2X 1/5 receptors was found (Lewis and Evans, 2000). 2',39-O-(2,4,6-Trinitrophenyl)-ATP blocked the responses of rat mesenteric arteries to a,b-meATP (Lewis et al, 1998), whereas in mouse mesenteric arteries, the contractile response to a,b-meATP was blocked by the P2X 1 receptorantagonist NF023 (1,3,5-trisodium 8-{[3-({[3-({4,6,8-tris[(sodiooxy)sulfonyl]naphthalen-1-yl}carbamoyl)phenyl]carbamoyl}amino)benzene]amido}naphthalene-1,3,5-trisulfonate) (Koltsova et al, 2009), suggesting that P2X 1 receptors were involved. Studies with P2X 1 receptor knockout mice established that P2X 1 and P2Y 6 -like receptors mediate sympathetic neurogenic vasoconstriction of mouse mesenteric arteries (Vial and Evans, 2002).…”