Abstract 525: Adult Inducible Deletion of Endothelial Hypoxia-inducible Factor-2α Exaggerates Myocardial Infarction Induced Heart Failure and Cardiac Microvascular Barrier Dysfunction

Abstract

Background: Myocardial ischemia occurs during myocardial infarction results in the stabilization of Hypoxia-inducible factors (HIFs). Hif2α expresses profoundly in vascular endothelial cells (EC), and its embryonic deletion increases vessel permeability. It has been shown that HIF2a is protective from renal and pulmonary injury. However, the direct role of ecHIF2α in ischemia heart disease is unknown. We hypothesized that ecHIF2a expression in response to myocardial infarction (MI) protects cardiac barrier dysfunction and against heart failure. Methods and Results: We generated the Inducible endothelial-specific knockout mice (ecHIF2a -/- ) by crossing Hif2a flox/flox mice with Cre ERT2 mice under the VE-cadherin promoter. Followed with MI, ecHIF2a -/- mice displayed worsened cardiac function determined by echocardiography, and they had increased mortality as compared to the controls. In vitro, we used primary mouse cardiac microvascular endothelial cells (mCMVEC) from ecHIF2a -/- mouse hearts. We found that under hypoxia condition or 1mM Dimethyloxalylglycine treatment, the deficiency of HIF2a in the mCMVEC increased endothelial permeability determined by trans-endothelial electrical resistance. The knocking down of HIF2a in HUVECs induced by a HIF2a siRNA led to impaired tube formation accessed by the significant reduction in total node counts, junctions, meshes, and full tube length compared to control-siRNA treated cells. HIF2α deletion and hypoxia both reduced endothelial cell migration, and interestingly, the retarded HIF2α-/- ECs migration seems to be independent of hypoxia. Moreover, apoptosis assay showed that ecHIF2a -/- ECs increased cell early apoptotic stage compared to WT in hypoxic conditions, but not in normoxia indicating the critical role of HIF2α in ECs survival during cardiac ischemia. Finally, several increased markers of inflammation, such as ICAM-1 and VCAM-1, are associated with HIF2a deletion. Conclusion: These data revealed an essential role of HIF2α in protecting cardiac remodeling in response to MI, which might through promoting endothelial cell migration, barrier function, as well as vascularization. Thus, HIF2α is a potential therapeutic target in the treatment of ischemic heart disease.