Vascular Hypoxic Preconditioning Relies on TRPV4-Dependent Calcium Influx and Proper Intercellular Gap Junctions Communication

Abstract

Objective-We investigated the impact of hypoxia-reoxygenation on endothelial relaxation and aimed to clarify the role of transient receptor potential cation channels V4 (TRPV4) and gap junctions in the protective effect associated with hypoxic preconditioning on the vascular function. Methods and Results-By mimicking ischemia-reperfusion in C57BL/6 male mice in vivo, we documented a reduced NOmediated relaxation and an increased endothelium-derived hyperpolarization (EDH[F])-mediated relaxation. Hypoxic preconditioning, however, restored NO relaxation and further improved the EDH(F) response. We also examined specifically 2 major effectors of the EDH(F) pathway, transient receptor potential cation channels V4 and connexins. We found that in endothelial cells, expression and activity of transient receptor potential cation channels V4 were increased by hypoxic stimuli independently of preconditioning which was interestingly associated with an increase of structural caveolar component caveolin-1 at membrane locations. Gap junctions, however, seemed to directly support EDH(F)-driven preconditioning as connexin 40 and connexin 43 expression increased and as in vivo carbenoxolone treatment completely inhibited the EDH(F) pathway and significantly reduced the protection afforded by preconditioning for the concomitant NO-mediated relaxation. Conclusion-Our

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

“…This metabolic requirement is reminiscent of 'preconditioning' of cardiac [21] and vascular cells [22], i.e. the prosurvival mechanisms against ischaemic insults conferred by challenges of repeated short periods of ischaemia.…”

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...…”

Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries

“…However, the present results do not allow further speculation as to the molecular events connecting TRP channels to the activation of the non-neuronal cholinergic system in the endothelium. As well as in response to hypothermia, TRPV4 activation can preserve vasodilatation under hypoxic conditions and restore NO-mediated relaxations during hypoxic preconditioning (Rath et al, 2012). Thus, TRPV4 channels may play a vascular protective role under pathologic conditions.…”