Increased myoendothelial feedback is associated with increased connexin37 and <scp>IK</scp>1 channel expression in mesenteric arteries of diet‐induced hyperhomocysteinemic mice

Looft‐Wilson, Robin; Goodell, Cara R.; Mutch, Christina A.; Mutchler, Stephanie; Miller, Kayla L.; Guraya, Monique

doi:10.1111/micc.12398

Cited by 6 publications

(5 citation statements)

References 58 publications

(129 reference statements)

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“…Additionally, we found the presence of expression (using western blot) of both of these isoforms in whole mouse mesenteric arteries (Looft‐Wilson et al. ). However, there is currently no evidence that these NOS isoforms are involved in flow‐induced vasodilation in mouse mesenteric arteries.…”

Section: Discussionmentioning

confidence: 68%

“…endothelium of mouse mesenteric arteries (Takaki et al 2008;Silva et al 2016), and iNOS can be induced in endothelium with knock-out of the other NOS isoforms (Takaki et al 2008). Additionally, we found the presence of expression (using western blot) of both of these isoforms in whole mouse mesenteric arteries (Looft-Wilson et al 2017). However, there is currently no evidence that these NOS isoforms are involved in flow-induced vasodilation in mouse mesenteric arteries.…”

Section: Limitationsmentioning

confidence: 69%

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

et al. 2018

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In arteries, endothelium‐dependent vasodilatory agonists and flow‐induced shear stress cause vasodilation largely by activation of the endothelial enzyme eNOS, which generates nitric oxide that relaxes vascular smooth muscle. Agonists activate eNOS in part through increased phosphorylation at Ser1179 and decreased phosphorylation at Thr495. We previously found that preconstriction of intact, isolated mouse mesenteric arteries with phenylephrine also caused increased Ser1179 and decreased Thr495 eNOS phosphorylation, and sequential treatment with the vasodilatory agonist acetylcholine did not cause any further change in phosphorylation at these sites, despite producing vasodilation. The present study tests the hypothesis that luminal flow in these arteries preconstricted with phenylephrine also produces vasodilation without phosphorylation changes at these sites. First‐order mesenteric arteries, isolated from male C57/BL6 mice (7–20 weeks of age) anesthetized with pentobarbital (50 mg/kg, i.p.), were cannulated, pressurized, and treated with stepped increases in luminal flow (15–120 μL/min). Flow resulted in dilation that plateaued at ~60 μL/min (31.3 ± 3.0% dilation) and was significantly (P < 0.001) NOS‐dependent at all flow rates (determined by 10−4 mol/L L‐NAME treatment). In separate arteries, preconstriction with phenylephrine (10−5 mol/L) resulted in increased eNOS phosphorylation at Ser1179 (P < 0.05) and decreased phosphorylation at Thr495, but subsequent flow at 60 μL/min for 5 or 15 min did not cause further changes in phosphorylation, despite causing dilation. Thus, flow‐induced dilation does not require changes in these eNOS phosphorylation sites beyond those induced by alpha1‐adrenergic stimulation with phenylephrine, indicating that eNOS is activated by other mechanisms during acute flow‐induced dilation of preconstricted arteries.

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Section: Discussionmentioning

confidence: 68%

Section: Limitationsmentioning

confidence: 69%

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

et al. 2018

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“…) studies on InsP 3 –IK Ca channel‐mediated myoendothelial feedback have utilized arteries from rats, with only one recent study describing this pathway in arteries from mice (Looft‐Wilson et al . ).…”

Section: Discussionmentioning

confidence: 97%

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

Wei

Lunn

Tam

et al. 2018

The Journal of Physiology

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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.

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“…Interestingly, connexins at the myoendothelial junctions are subject to functional regulation (Straub et al, 2010;Westcott and Segal, 2013), which may provide an explanation for the discrepant in vivo findings. Although significant charge transfer through MEGJ was not convincingly demonstrated in vivo, significant contributions of myoendothelial coupling to vascular function may well be of importance, for example the transfer of intracellular messengers (Looft-Wilson et al, 2017;Biwer et al, 2018;Wei et al, 2018;Wilson et al, 2019;Pohl, 2020).…”

Section: Lack Of Evidence For Charge Transmission By Myoendothelial Cmentioning

confidence: 98%

“…We describe in this short review the structural requirements and illuminate the experimental evidence obtained in vivo that argues against or in favor of the hypothesis that EDHF indeed is an EDH-type dilation rather than being a freely diffusible molecule. Other important functions of myoendothelial coupling, including the transfer of calcium or intracellular messengers, such as inositol-1,4,5-triphosphate (IP3) that modulate vascular responses (Looft-Wilson et al, 2017;Biwer et al, 2018; FIGURE 1 | A multitude of endothelial molecules and mechanisms (depicted in yellow boxes) relax vascular smooth muscle. The well-accepted chemical mediators such as nitric oxide (NO) and prostaglandins (PG) are shown, and a variety of substances that have been suggested to underly the endothelium-dependent hyperpolarization (EDH)-type dilation.…”

Section: Introductionmentioning

confidence: 99%

Endothelium-Derived Hyperpolarizing Factor and Myoendothelial Coupling: The in vivo Perspective

Schmidt

Wit

2020

Front. Physiol.

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The endothelium controls vascular tone adopting blood flow to tissue needs. It releases chemical mediators [e.g., nitric oxide (NO), prostaglandins (PG)] and exerts appreciable dilation through smooth muscle hyperpolarization, thus termed endothelium-dependent hyperpolarization (EDH). Initially, EDH was attributed to release of a factor, but later it was suggested that smooth muscle hyperpolarization might be derived from radial spread of an initial endothelial hyperpolarization through heterocellular channels coupling these vascular cells. The channels are indeed present and formed by connexins that enrich in gap junctions (GJ). In vitro data suggest that myoendothelial coupling underlies EDH-type dilations as evidenced by blocking experiments as well as simultaneous, merely identical membrane potential changes in endothelial and smooth muscle cells (SMCs), which is indicative of coupling through ohmic resistors. However, connexin-deficient animals do not display any attenuation of EDH-type dilations in vivo, and endothelial and SMCs exhibit distinct and barely superimposable membrane potential changes exerted by different means in vivo. Even if studied in the exact same artery EDH-type dilation exhibits distinct features in vitro and in vivo: in isometrically mounted vessels, it is rather weak and depends on myoendothelial coupling through connexin40 (Cx40), whereas in vivo as well as in vitro under isobaric conditions it is powerful and independent of myoendothelial coupling through Cx40. It is concluded that EDH-type dilations are distinct and a significant dependence on myoendothelial coupling in vitro does not reflect the situation under physiologic conditions in vivo. Myoendothelial coupling may act as a backup mechanism that is uncovered in the absence of the powerful EDH-type response and possibly reflects a situation in a pathophysiologic environment.

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Increased myoendothelial feedback is associated with increased connexin37 and IK1 channel expression in mesenteric arteries of diet‐induced hyperhomocysteinemic mice

Abstract: Diet-induced HHcy enhanced myoendothelial feedback, and increased Cx37 and IK1 expression may contribute. nNOS or iNOS did not upregulate to compensate for decreased eNOS, and they had little involvement in vasomotor function.

Cited by 6 publications

References 58 publications

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

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

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

Endothelium-Derived Hyperpolarizing Factor and Myoendothelial Coupling: The in vivo Perspective

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