Cardioprotection and improvement in endothelial-dependent vasodilation during late-phase of whole body hypoxic preconditioning in spontaneously hypertensive rats via VEGF and endothelin-1

Abstract

The present study was designed to investigate the effect of late phase of whole body hypoxic preconditioning on endothelial-dependent vasorelaxation and cardioprotection from ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Hypoxic preconditioning was performed by subjecting rats to four episodes of alternate exposure to low O2 (8%) and normal air O2 of 10 min each. After 24 h, the mesenteric arteries and hearts were isolated to determine the vascular function and cardioprotection from ischemia-reperfusion (I/R) injury on the Langendorff apparatus. There was a significant impairment in acetylcholine-induced relaxation in norepinephrine precontracted arteries (endothelium-dependent function) and increase in I/R-induced myocardial injury in SHR in comparison to Wistar Kyoto rats (WKY). However, hypoxic preconditioning significantly restored endothelium-dependent relaxation in SHR and attenuated I/R injury in both SHR and WKY. Hypoxic preconditioning also led to an increase in the levels of endothelin-1 (not endothelin-2 or −3), vascular endothelial growth factor-A (VEGF-A) and HIF-1α levels. Pretreatment with bevacizumab (anti-VEGF-A) and bosentan (endothelin receptor blocker) significantly attenuated hypoxic preconditioning-induced restoration of endothelium-dependent relaxation and cardioprotection from I/R injury. These interventions also attenuated the levels of VEGF-A and HIF-1α without modulating the endothelin-1 levels. It may be concluded that an increase in the endothelin-1 levels with a subsequent increase in HIF-1α and VEGF expression may possibly contribute in improving endothelium-dependent vasorelaxation and protecting hearts from I/R injury in SHR during late phase of whole body hypoxic preconditioning.