The TWIK related K þ channel TREK1 is an important member of the class of two-pore-domain K þ channels. It is a background K þ channel and is regulated by hormones, neurotransmitters, intracellular pH and mechanical stretch. This work shows that TREK1 is present both in mesenteric resistance arteries and in skin microvessels. It is particularly well expressed in endothelial cells. Deletion of TREK1 in mice leads to an important alteration in vasodilation of mesenteric arteries induced by acetylcholine and bradykinin. Iontophoretic delivery of acetylcholine and bradykinin in the skin of TREK1 þ / þ and TREK1 À/À mice also shows the important role of TREK1 in cutaneous endothelium-dependent vasodilation. The vasodilator response to local pressure application is also markedly decreased in TREK1 À/À mice, mimicking the decreased response to pressure observed in diabetes. Deletion of TREK1 is associated with a marked alteration in the efficacy of the G-protein-coupled receptor-associated cascade producing NO that leads to major endothelial dysfunction.
AimsOur objective was to investigate whether pro-oxidant properties of ascorbic acid (AA) and tetrahydrobiopterin (BH4) modulate endothelium-dependent, electrotonically mediated arterial relaxation.Methods and resultsIn studies with rabbit iliac artery (RIA) rings, NO-independent, endothelium-derived hyperpolarizing factor (EDHF)-type relaxations evoked by the sarcoplasmic endoplasmic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid and the G protein-coupled agonist acetylcholine (ACh) were enhanced by AA (1 mM) and BH4 (200 µM), which generated buffer concentrations of H2O2 in the range of 40–80 µM. Exogenous H2O2 potentiated cyclopiazonic acid (CPA)- and ACh-evoked relaxations with a threshold of 10–30 µM, and potentiation by AA and BH4 was abolished by catalase, which destroyed H2O2 generated by oxidation of these agents in the organ chamber. Adventitial application of H2O2 also enhanced EDHF-type dilator responses evoked by CPA and ACh in RIA segments perfused intraluminally with H2O2-free buffer, albeit with reduced efficacy. In RIA rings, both control relaxations and their potentiation by H2O2 were overcome by blockade of gap junctions by connexin-mimetic peptides (YDKSFPISHVR and SRPTEK) targeted to the first and second extracellular loops of the dominant vascular connexins expressed in the RIA. Superoxide dismutase attenuated the potentiation of EDHF-type relaxations by BH4, but not AA, consistent with findings demonstrating a differential role for superoxide anions in the generation of H2O2 by the two agents.ConclusionPro-oxidant effects of AA and BH4 can enhance the EDHF phenomenon by generating H2O2, which has previously been shown to amplify electrotonic hyperpolarization-mediated relaxation by facilitating Ca2+ release from endothelial stores.
The existence of a cutaneous pressure-induced vasodilation (PIV) has recently been reported. This paper proposes a signal processing methodology to improve PIV knowledge. Temporal variations of laser Doppler signals rhythmic activities are first analyzed on anesthetized rats. The results lead to a method that provides a better PIV understanding.
In the skin of humans and rodents, local pressure induces localized cutaneous vasodilation, which may be protective against pressure-induced microvascular dysfunction and lesion formation. Once activated by the local pressure application, capsaicin-sensitive nerve fibers release neuropeptides that act on the endothelium to synthesize and release nitric oxide (NO) and prostaglandins, leading to the development of the cutaneous pressure-induced vasodilation (PIV). The present study was undertaken to test in vivo the hypothesis that PIV is mediated or modulated by differential activation of K+ channels in anesthetized rats using pharmacological methods. Local pressure was applied at 11.1 Pa/s. Endothelium-independent and -dependent vasodilation were tested using iontophoretic delivery of sodium nitroprusside (SNP) and acetylcholine (ACh), respectively, and was correlated with PIV response. PIV was reduced after systemic administration of tetraethylammonium (a nonspecific K+ channel blocker), iberiotoxin [a specific large-conductance Ca2+-activated K+ (BKCa) channel blocker], and glibenclamide [a specific ATP-sensitive K+ (KATP) channel blocker], whereas PIV was unchanged by apamin (a specific small-conductance Ca2+-activated K+ channel blocker) and 4-aminopyridine (a specific voltage-sensitive K+ channel blocker). The responses to SNP and ACh were reduced by iberiotoxin but were unchanged by glibenclamide. We conclude that the cellular mechanism of PIV in skin involves BKCa and KATP channels. We suggest that the opening of BKCa and KATP channels contributes to the hyperpolarization of vascular smooth muscle cells to produce PIV development mainly via the NO and prostaglandin pathways, respectively.
Endothelial dysfunction is a major risk factor for vascular complications associated with diabetes. The purpose of this study was to evaluate the possible link between oxidative stress and alteration in calcium homeostasis in dysfunctional endothelial cells from db/db diabetic mice, 20 or 45 week old. Impaired flow‐induced dilation in mesenteric arteries and acetylcholine‐induced relaxation in aorta due to a decreased nitric oxide (NO) bioavailability were already shown in this model. For this study, mice aortic endothelial cells (MAEC) were isolated from vessel explants. Oxidative stress and Ca2+ homeostasis in MAEC were simultaneously recorded with DHE and Fura‐2 probes using an inverted epi‐fluorescence microscope. Compared to control mice, oxidative stress in MAEC from db/db mice increased with age leading to a progressive alteration of Ca2+ homeostasis, characterized by a rise in basal cytosolic calcium and a decrease in amplitude of acetylcholine‐induced calcium peak. Interestingly, a NO donor reduced oxidative stress and improved calcium signaling in endothelial cells from db/db mice. These results suggest that reduced NO bioavailability contributes to oxidative stress and abnormal calcium homeostasis in endothelial cells during progression of diabetes.
NO controls the activity of canonical transient receptor potential channel (TRPC) in endothelial cells. Our group already provided evidences that reduced NO bioavailability was directly linked to increased basal cytosolic Ca2+ in a cellular model of endothelial dysfunction. The aim of this study was to evaluate the role of TRPC3 channels in Ca2+ homeostasis of aortic porcine endothelial cells (PAEC). In PAEC at P1, producing NO, specific inhibition of TRPC3 by Pyr3 induced a concentration‐dependent decrease in Ca2+ entry as shown by reduced basal [Ca2+]i and decreased Ca2+ peak amplitude in response to bradykinin. Similar modifications were observed in the presence of Orai1 inhibitor or in a Ca2+‐free buffer while OAG, a specific TRPC3 activator, didn't modify Ca2+ homeostasis. In dysfunctional PAEC at P4, model of endothelial dysfunction associated with basal increased of [Ca2+]i, Pyr3 normalized the basal [Ca2+]i in a concentration‐dependent manner while the activation of TRPC3 by OAG over increased it. These results indicate that calcium entry by TRPC3 and Orai1 channels is involved in regulation of cytosolic calcium in functional endothelial cells. In dysfunctional endothelial cells with limited NO production, an increased expression or activity of TRPC3 may participate to the abnormal Ca2+ homeostasis
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