Endothelial deletion of hypoxia-inducible factor-2α (HIF-2α) alters vascular function and tumor angiogenesis
Endothelial deletion of hypoxia-inducible factor-2α (HIF-2α) alters vascular function and tumor angiogenesis
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DOI：
10.1182/blood-2008-12-193581
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发表时间：
2009-07-09
期刊：
影响因子：
20.3
通讯作者：
Keith, Brian
中科院分区：
文献类型：
--
作者：
Skuli, Nicolas;Liu, Liping;Keith, Brian
缺氧诱导因子-2 α（HIF-2 α）在胚胎血管内皮细胞（EC）中高度表达，并激活靶基因的表达，其产物调节血管功能和血管生成。在这份报告中，我们描述了一个遗传模型，旨在测试删除HIF-2 α在小鼠内皮细胞的生理后果。令人惊讶的是，HIF-2 α缺陷EC的小鼠发育正常，但表现出多种表型，包括血管通透性增加，异常内皮细胞超微结构和肺动脉高压。此外，这些动物表现出与增加的缺氧应激和肿瘤细胞凋亡相关的肿瘤血管生成缺陷。永生化的HIF-2 α缺陷的EC显示与细胞外基质蛋白的粘附减少，并且表达编码纤连蛋白、整合素、内皮素B受体、血管生成素2和δ样配体4（Dll 4）的转录物的水平降低。总之，这些数据确定了血管内皮细胞中HIF-2 α的独特细胞自主功能。（血。2009; 114：469-477）
Hypoxia-inducible factor-2 alpha (HIF-2 alpha) is highly expressed in embryonic vascular endothelial cells (ECs) and activates the expression of target genes whose products modulate vascular function and angiogenesis. In this report, we describe a genetic model designed to test the physiologic consequences of deleting HIF-2 alpha in murine endothelial cells. Surprisingly, mice with HIF-2 alpha-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-2 alpha-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). Together, these data identify unique cell-autonomous functions for HIF-2 alpha in vascular endothelial cells. (Blood. 2009; 114: 469-477)