Spreading vasodilatation in the murine microcirculation: attenuation by oxidative stress‐induced change in electromechanical coupling

Abstract

Regulation of blood flow in microcirculatory networks depends on spread of local vasodilatation to encompass upstream arteries; a process mediated by endothelial conduction of hyperpolarization. Given that endothelial coupling is reduced in hypertension, we used hypertensive Cx40ko mice, in which endothelial coupling is attenuated, to investigate the contribution of the renin-angiotensin system and reduced endothelial cell coupling to conducted vasodilatation of cremaster arterioles in vivo. When the endothelium was disrupted by light dye treatment, conducted vasodilatation, following ionophoresis of acetylcholine, was abolished beyond the site of endothelial damage. In the absence of Cx40, sparse immunohistochemical staining was found for Cx37 in the endothelium, and endothelial, myoendothelial and smooth muscle gap junctions were identified by electron microscopy. Hyperpolarization decayed more rapidly in arterioles from Cx40ko than wild-type mice. This was accompanied by a shift in the threshold potential defining the linear relationship between voltage and diameter, increased T-type calcium channel expression and increased contribution of T-type (3 μmol l(-1) NNC 55-0396), relative to L-type (1 μmol l(-1) nifedipine), channels to vascular tone. The change in electromechanical coupling was reversed by inhibition of the renin-angiotensin system (candesartan, 1.0 mg kg(-1) day(-1) for 2 weeks) or by acute treatment with the superoxide scavenger tempol (1 mmol l(-1)). Candesartan and tempol treatments also significantly improved conducted vasodilatation. We conclude that conducted vasodilatation in Cx40ko mice requires the endothelium, and attenuation results from both a reduction in endothelial coupling and an angiotensin II-induced increase in oxidative stress. We suggest that during cardiovascular disease, the ability of microvascular networks to maintain tissue integrity may be compromised due to oxidative stress-induced changes in electromechanical coupling.

Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent calcium channel function in rat uterine radial artery

“…3, E and F). Previous studies suggest that NNC 55-0396 blocks both nifedipine-sensitive and -insensitive voltage-dependent Ca 2ϩ currents (28,32). However, NNC 55-0396 T-channel specificity has been supported via studies in Ca v 3.1 knockout mice (56), noting that the present study was conducted after arteries were exposed to nifedipine to eliminate potential effects of NNC 55-0396 on Ca v 1.2.…”

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…Endothelium-derived hyperpolarizing factor Edwards et al, 1998;Hutcheson et al, 1999;Yamamoto et al, 1999;Beny and Schaad, 2000;Kansui et al, 2004;Mather et al, 2005;Rath et al, 2012;Howitt et al, 2013Vascular conducted responses Kruger et al, 2002Dora et al, 2003b;Simon and McWhorter, 2003;Wolfle et al, 2007;Duling, 2008 Feedback on vasoconstriction Dora et al, 1997;Straub et al, 2011 Smooth muscle cell proliferation Chadjichristos et al, 2006;Liao et al, 2007;Johnstone et al, 2010;Zhong et al, 2012 a Smooth muscle cell differentiation Kwak et al, 2003;Chadjichristos et al, 2008;Shen et al, 2010;Gairhe et al, 2011Gairhe et al, , 2012 Endothelial cell proliferation Larson et al, 1997;Kwak et al, 2001;Yeh et al, 2006;Nakano et al, 2008;Wang et al, 2008 c Endothelial cell dysfunction Xie and Hu, 1994;Makino et al, 2008;Chadjichristos et al, 2010;Wang et al, 2012;Ebong and Depaola, 2013 Endothelial cell migration Pepper and Meda, 1992;Pepper et al, 1989;Kwak et al, 2001 a Evidence that gap junction independent pathways are involved in this regulation . b Evidence that although connexin expression and/or gap junction communication levels correlated to disease they do not appear to be directly linked...…”

Role of connexins and pannexins in cardiovascular physiology

“…Thus, they are involved in relaxation induced by endothelium-dependent hyperpolarization [125][126][127][128][129][130][131]. Furthermore, hyperpolarization evoked in either ECs or VSMCs can spread a relatively large distance from its source to neighboring cells via gap junctions causing remote dilatation [132][133][134][135][136]. Importantly, gap junction-induced spread of dilatation is not only observed in the direction of blood flow, as would be the case for soluble factors secreted in blood, but also in retrograde direction.…”

“…In this respect, arterioles of Cx40-deficient mice display irregular vasomotion and spontaneous vessel closure [137]. Conducted dilatation appeared to be reduced in arterioles from Cx40-deficient mice, suggesting that Cx40 is of critical importance for this phenomenon [133,138]. A more recent study addressed possible differences between the spread of hyperpolarization induced by an agonist, such as acetylcholine, or by an opener of potassium channels, like pinacidil [135].…”