Vasoconstrictor stimulus determines the functional contribution of myoendothelial feedback to mesenteric arterial tone

Abstract

Constriction of isolated resistance arteries in response to α -adrenoceptor agonists is limited by reciprocal engagement of inhibitory endothelial mechanisms via myoendothelial feedback. In the current model of feedback, agonist stimulation of smooth muscle cells results in localized InsP -dependent Ca transients that activate endothelial IK channels. The subsequent hyperpolarization of the endothelial membrane potential then feeds back to the smooth muscle to limit further reductions in vessel diameter. We hypothesized that the functional contribution of InsP -IK channel-mediated myoendothelial feedback to limiting arterial diameter may be influenced by the nature of the vasoconstrictor stimulus. To test this hypothesis, we investigated the functional role of myoendothelial feedback in modulating responses of rat mesenteric resistance arteries to the adrenoceptor agonist noradrenaline, the thromboxane A mimetic U46619, increases in intravascular pressure and stimulation of perivascular sympathetic nerves. In isolated arteries, responses to noradrenaline and stimulation of sympathetic nerves, but not to U46619 and increases in intravascular pressure, were modulated by IK channel-dependent myoendothelial feedback. In the intact mesenteric bed perfused under conditions of constant flow, responses to exogenous noradrenaline were modulated by myoendothelial feedback, but shear stress-induced release of NO and activation of endothelial SK channels appeared to be the primary mediators of endothelial modulation of vasoconstriction to agonists and nerve stimulation. Thus, we propose that myoendothelial feedback may contribute to local control of diameter within arterial segments, but at the level of the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction.

Flow does not alter eNOS phosphoryation at Ser1179 or Thr495 in preconstricted mouse mesenteric arteries

“…It is currently unknown whether preconstriction with vasoconstrictors other than phenylephrine would result in myoendothelial-dependent eNOS phosphorylation as observed in this study, because this event has only been reported with this vasoconstrictor (Looft-Wilson et al 2013). It might be predicted, however, that only vasoconstrictor stimuli which result in smooth muscle IP 3 generation may activate and/or phosphorylate NOS via myoendothelial communication because a recent study indicates that only some vasoconstrictors induce myoendothelial feedback and this ability seems to be IP 3 -dependent (Wei et al 2018). Specifically, it has been shown that NOS-dependent myoendothelial feedback occurs with phenylephrine, norepinephrine, and high-frequency perivascular nerve stimulation in rat mesenteric arteries (Kerr et al 2015;Wei et al 2018).…”

“…; Wei et al. ). Based on evidence from small arteries/arterioles of several rodent species, these stimuli act exclusively on smooth muscle through alpha 1 ‐adrenergic receptor stimulation (Jackson et al.…”

“…It might be predicted, however, that only vasoconstrictor stimuli which result in smooth muscle IP 3 generation may activate and/or phosphorylate NOS via myoendothelial communication because a recent study indicates that only some vasoconstrictors induce myoendothelial feedback and this ability seems to be IP 3 ‐dependent (Wei et al. ). Specifically, it has been shown that NOS‐dependent myoendothelial feedback occurs with phenylephrine, norepinephrine, and high‐frequency perivascular nerve stimulation in rat mesenteric arteries (Kerr et al.…”

“…In contrast, neither the vasoconstrictor U46619 (a thromboxane A 2 mimetic) nor myogenic tone induce myoendothelial feedback in rat mesenteric arteries, and these stimuli do not induce IP 3 signaling (Wei et al. ). The ability of vasoconstrictors, other than phenylephrine, to phosphorylate eNOS via myoendothelial communication would need to be specifically tested in our model, and would be experimentally challenging given that some vasoconstrictors (e.g., U46619, 5‐HT) may act directly on endothelial cells to activate eNOS.…”

“…It might be predicted, however, that only vasoconstrictor stimuli which result in smooth muscle IP 3 generation may activate and/or phosphorylate NOS via myoendothelial communication because a recent study indicates that only some vasoconstrictors induce myoendothelial feedback and this ability seems to be IP 3 -dependent (Wei et al 2018). Specifically, it has been shown that NOS-dependent myoendothelial feedback occurs with phenylephrine, norepinephrine, and high-frequency perivascular nerve stimulation in rat mesenteric arteries (Kerr et al 2015;Wei et al 2018). Based on evidence from small arteries/arterioles of several rodent species, these stimuli act exclusively on smooth muscle through alpha 1adrenergic receptor stimulation (Jackson et al 2008;Nausch et al 2012) and generate smooth muscle IP 3 that stimulates endothelial calcium release, hyperpolarization, and NOS generation via myoendothelial gap junction communication (Kansui et al 2008;Kerr et al 2015).…”