The study of hypoxia implications in endothelium

Abstract

Hypoxia is a condition that occurs due to the decline in oxygen concentrations below the physiological levels. Hypoxia causes endothelial dysfunctions, which are highly implicated in various cardiovascular disorders. The overall focus of this thesis is to investigate the role of hypoxia in endothelial remodeling in relation to nitric oxide (NO) and reactive oxygen species (ROS). Our hypothesis is that hypoxia attenuates NO production by elevating ROS and inactivating endothelial nitric oxide synthase (eNOS) and thereby contributes to endothelial dysfunctions. The present work addresses the effect of hypoxia in causing endothelial damage, specifically endothelial barrier dysfunctions. In the first part of this research we have studied the implications of hypoxia in in-ovo blood vessels using artery ligation model which showed analtered redox status with elevated superoxide and peroxynitrite levels and reduced glutathione levels in tissues and endothelial cells (EC) specific to the ligated region. Further we employed cell based models to study the effect of hypoxia on endothelial morphology and barrier dysfunctions in relation to actin rearrangements and NO production. The study provides evidence that elevated level of ROS and low bioavailability of NO under hypoxia contribute to leaky endothelium. The present study also explained the possible mechanism for low bioavailability of NO production under hypoxia by addressing the disturbances in proteinprotein interactions and compartmentalization of eNOS within the membrane pools. The present work concludes that low bioavailability of NO under hypoxia in endothelial cells is either due to inactivation of the eNOS which is a predominant source of NO production or due to quenching of NO by ROS moieties. The results of the work direct further investigations into the mechanism of hypoxia mediated barrier dysfunctions and the use of NO donors and ROS scavengers as potential therapeutic strategies for hypoxia implicated clinical conditions. newline