Mechanotransduction Drives Post Ischemic Revascularization Through K_ATP Channel Closure and Production of Reactive Oxygen Species

Abstract

Aims: We reported earlier that ischemia results in the generation of reactive oxygen species (ROS) via the closure of a K ATP channel which causes membrane depolarization and NADPH oxidase 2 (NOX2) activation. This study was undertaken to understand the role of ischemia-mediated ROS in signaling. Results: Angiogenic potential of pulmonary microvascular endothelial cells (PMVEC) was studied in vitro and in the hind limb in vivo. Flow adapted PMVEC injected into a Matrigel matrix showed significantly higher tube formation than cells grown under static conditions or cells from mice with knockout of K ATP channels or the NOX2. Blocking of hypoxia inducible factor-1 alpha (HIF-1a) accumulation completely abrogated the tube formation in wild-type (WT) PMVEC. With ischemia in vivo (femoral artery ligation), revascularization was high in WT mice and was significantly decreased in mice with knockout of K ATP channel and in mice orally fed with a K ATP channel agonist. In transgenic mice with endothelial-specific NOX2 expression, the revascularization observed was intermediate between that of WT and knockout of K ATP channel or NOX2. Increased HIF-1a activation and vascular endothelial growth factor (VEGF) expression was observed in ischemic tissue of WT mice but not in K ATP channel and NOX2 null mice. Revascularization could be partially rescued in K ATP channel null mice by delivering VEGF into the hind limb. Innovation: This is the first report of a mechanosensitive ion channel (K ATP channel) initiating endothelial signaling that drives revascularization. Conclusion: The K ATP channel responds to the stop of flow and activates signals for revascularization to restore the impeded blood flow. Antioxid. Redox Signal. 20,[872][873][874][875][876][877][878][879][880][881][882][883][884][885][886]

Mechanosignaling in the vasculature: emerging concepts in sensing, transduction and physiological responses

“…Likewise, mechanical signaling or mechanotransduction involves the activation of receptors. Analogous to chemical signaling or chemotransduction, physical forces trigger a signaling process by which mechanical stimuli are translated into a biochemical and eventual physiological response (9,16,49,80).This symposium was organized to present mechanosignaling and related issues at the session titled "Mechanosignaling in the Vasculature: Shear stress, Endothelium and Redox Signaling" at the First Pan American Physiological Conference at Iguassu Falls in August 2014. Sponsored by the American Physiological Society, this symposium focused on various sites of vascular mechanotransduction in the cardiovascular system, primarily the vascular endothelium and the cardiomyocytes (primary sites for sensing blood flow and cardiac contractility respectively).…”

“…Likewise, mechanical signaling or mechanotransduction involves the activation of receptors. Analogous to chemical signaling or chemotransduction, physical forces trigger a signaling process by which mechanical stimuli are translated into a biochemical and eventual physiological response (9,16,49,80).…”

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation

“…Lung hypoxia can occur if lungs are permitted to collapse or remain unventilated for prolonged periods. Injury under these conditions may arise from complex signaling cascades involving both hypoxia (and reoxygenation) and ischemia (and reoxygenation) (16). An earlier clinical practice had been to ventilate lungs during harvest and storage.…”

“…For reasons described below, we consider this to be an inadequate model for study of physiological events. Our laboratory during the past two decades has evaluated endothelial mechanotransduction using intact lungs as well as isolated cells that are exposed to abrupt cessation of blood flow (3,15,19,20,25,79,94,125). Thus these studies have utilized a physiological model that has relevance for understanding the effects of lung ischemia followed by reperfusion (I/R) as occurs clinically following pulmonary embolism, during cardiopulmonary bypass (CPB), and also during lung transplantation.…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…8). Collectively, the activation of these signaling cascades thus could lead to vasodilation, cell proliferation, injury, or other consequences (17,26,73,142). As ROS and NO are able to modulate thiol groups of many ion channels (1,27,101) including the K ATP channel (21,64,138), which are potentially involved in membrane potential regulation and downstream signaling, we propose that a feedback loop may exist linking membrane potential, ion channel regulation (by S-glutathionylation or S-nitrosylation), The modification of one cysteine by S-glutathionylation has an allosteric effect on another cysteine residue at a different place, modulating its reactivity to S-nitrosylation.…”