Abstract SY16-01: The impact of oxygen availability on angiogenesis: HIF/Notch pathway interactions

Abstract

Abstract The therapeutic manipulation of angiogenesis holds great promise for treating diverse pathological conditions including cancer, macular degeneration, atherosclerosis, and peripheral arterial disease (PAD). However, the ability to reliably inhibit (or promote) angiogenesis in clinical settings requires a thorough appreciation of the complex molecular events that coordinate vessel sprouting and remodeling. It is well established that these processes are strongly influenced by localized O2 deprivation (hypoxia), which can arise as a consequence of ischemic insult or rapid cell division during solid tumor growth. Elucidating the mechanisms by which hypoxic stress modulates the activity of vascular endothelial cells (ECs) is therefore critical to our understanding of disease-associated angiogenesis. Hypoxia-inducible factor-2α (HIF-2α) is highly expressed in embryonic vascular endothelial cells (ECs) and activates the expression of target genes whose products modulate vascular function and angiogenesis. We have described previously a genetic model designed to test the physiologic consequences of deleting HIF-2α in murine endothelial cells. Surprisingly, mice with HIF-2α-deficient ECs developed normally but displayed a variety of phenotypes, including increased vessel permeability, aberrant endothelial cell ultrastructure, and pulmonary hypertension. Moreover, these animals exhibited defective tumor angiogenesis associated with increased hypoxic stress and tumor cell apoptosis. Immortalized HIF-2α-deficient ECs displayed decreased adhesion to extracellular matrix proteins and expressed reduced levels of transcripts encoding fibronectin, integrins, endothelin B receptor, angiopoietin 2, and delta-like ligand 4 (DLL4). Surprisingly, EC-specific HIF-2α deletion produced increased numbers of newly formed vessels in ischemic muscles and autochthonous tumors; however, these vessels fail to remodel effectively, thereby reducing overall vascular area, blood flow, and tissue oxygenation. Purified HIF-2α-deficient ECs display increased migration, invasion, and tube formation in vitro, as well as reduced hypoxic expression of important angiogenic molecules including angiopoietin 2 (Ang2) and adrenomedullin (ADM-1). Interestingly, similar effects on tumor angiogenesis were observed upon inhibition of the delta-like ligand 4 (Dll4)/Notch pathway, and we further demonstrate that HIF-2α specifically regulates hypoxic expression of Dll4, as well as downstream effectors of the Dll4/Notch pathway both in vivo and in vitro. Collectively, these data identify novel functions for HIF-2α, both in restricting angiogenic sprouting and promoting vascular remodeling, and identify specific molecular effectors underlying these effects, including Dll4, Ang2, and ADM-1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY16-01. doi:10.1158/1538-7445.AM2011-SY16-01