Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
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DOI：
10.1182/blood-2004-07-2958
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Semenza, GL
中科院分区：
文献类型：
--
作者：
Manalo, DJ;Rowan, A;Semenza, GL
缺氧诱导因子1（HIF-1）激活编码血管生成生长因子的基因的转录，所述血管生成生长因子由缺氧细胞分泌并刺激内皮细胞，导致血管生成。为了确定HIF-1是否也介导细胞对缺氧的自主反应，我们比较了在非缺氧与缺氧条件下培养的动脉内皮细胞和用编码β-半乳糖苷酶的腺病毒感染的非缺氧细胞与组成型活性形式的HIF-1 α（AdCA 5）的基因表达谱。有245个基因探针显示出至少1.5倍的表达增加，响应于缺氧和响应于AdCA 5; 325个基因探针显示出至少1.5倍的表达减少，响应于缺氧和响应于AdCA 5。最大类别的基因下调缺氧和AdCA 5编码的蛋白质参与细胞生长/增殖。缺氧和AdCA 5均上调的许多基因编码细胞因子/生长因子、受体和其他信号蛋白。转录因子占HIF-1调节基因的最大组。表明HIF-1控制内皮细胞对缺氧的转录反应网络。在非缺氧条件下用AdCA 5感染内皮细胞足以诱导增加基底膜侵袭和管形成，类似于缺氧诱导的反应。表明HIF-1介导内皮细胞的细胞自主活化。
Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis. To determine whether HIF-1 also mediates cell-autonomous responses to hypoxia, we have compared gene expression profiles in arterial endothelial cells cultured under nonhypoxic versus hypoxic conditions and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase versus a constitutively active form of HIF-1alpha (AdCA5). There were 245 gene probes that showed at least 1.5-fold increase in expression in response to hypoxia and in response to AdCA5; 325 gene probes showed at least 1.5-fold decrease in expression in response to hypoxia and in response to AdCA5. The largest category of genes down-regulated by both hypoxia and AdCA5 encoded proteins involved in cell growth/proliferation. Many genes up-regulated by both hypoxia and AdCA5 encoded cytolkines/growth factors, receptors, and other signaling proteins. Transcription factors accounted for the largest group of HIF-1-regulated genes. indicating that HIF-1 controls a network of transcriptional responses to hypoxia in endothelial cells. Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia. indicating that HIF-1 mediates cell-autonomous activation of endothelial cells.