HIF-2α-Haploinsufficient mice have blunted retinal neovascularization due to impaired expression of a proangiogenic gene battery
HIF-2α-Haploinsufficient mice have blunted retinal neovascularization due to impaired expression of a proangiogenic gene battery
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DOI：
10.1167/iovs.07-1469
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Garcia, Joseph A.
中科院分区：
文献类型：
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作者：
Dioum, Elhadji M.;Clarke, Stephen L.;Garcia, Joseph A.
目的。旨在表征 HIF-2 α 单倍体不足对新生小鼠视网膜新生血管形成和血管生成信号传导的影响。视网膜样本取自接受氧诱导视网膜病变 (OIR) 方案的 HIF-2 α 单倍剂量不足 (Epas1(+/-)) 和野生型 (Epas1(+/+)) 新生小鼠。 OIR 方案缺氧阶段开始后立即、12 小时或 5 天进行组织学和分子研究。在维持常氧或缺氧的小鼠脑内皮细胞中进行分子谱分析。转染研究评估了来自促血管生成基因的分离启动子区域对 HIF-1 α 或 -2 α 过表达的反应。结果。 Epas1(+/-) 小鼠在正常发育过程中视网膜血管系统没有表现出显着差异，但在 OIR 方案中视网膜新生血管形成减少。在Epas1(+/+) OIR 视网膜样品的缺氧阶段诱导了多种促血管生成因子，而Epas1(+/-) OIR 视网膜样品对这些相同因子的诱导缺失或减弱。缺氧后，小鼠脑内皮细胞中诱导了几种（但不是全部）促血管生成因子。在转染测定中，相对于 HIF-1 α，大多数促血管生成启动子区域优先被 HIF-2 α 激活。结论。 HIF-2α缺乏会导致OIR小鼠视网膜中新血管形成减少和多种促血管生成因子的诱导能力减弱。作者提出，HIF-2 α 是视网膜血管内皮细胞中促血管生成因子的主要调节因子，视网膜血管内皮细胞是表达 HIF-2 α 的视网膜的主要细胞类型。未来的研究将解决从这些研究中确定的 HIF-2 α 的分子和功能作用是否可以推广到涉及新血管形成的其他病理生理状态。
PURPOSE. To characterize the effect of HIF-2 alpha haploinsufficiency on retinal neovascularization and angiogenic signaling in neonatal mice.METHODS. Retinal samples were obtained from HIF-2 alpha-haploinsufficient (Epas1(+/-)) and wild-type (Epas1(+/+)) neonatal mice subjected to an oxygen-induced retinopathy (OIR) protocol. Histologic and molecular studies were performed immediately, 12 hours, or 5 days after initiation of the hypoxia phase of the OIR protocol. Molecular profiling was performed in mouse brain endothelial cells maintained in normoxia or hypoxia. Transfection studies assessed the response of isolated promoter regions from proangiogenic genes to HIF-1 alpha or -2 alpha overexpression.RESULTS. Epas1(+/-) mice exhibited no significant differences in retinal vasculature during normal development but had reduced retinal neovascularization in an OIR protocol. Multiple proangiogenic factors were induced during the hypoxia phase in Epas1(+/+) OIR retinal samples, whereas Epas1(+/-) OIR retinal samples had absent or blunted induction of these same factors. Several, but not all, proangiogenic factors were induced in mouse brain endothelial cells after hypoxia. In transfection assays, most proangiogenic promoter regions were preferentially activated by HIF-2 alpha relative to HIF-1 alpha.CONCLUSIONS. HIF-2 alpha deficiency results in reduced neovascularization and blunted inducibility of multiple proangiogenic factors in the retinas of mice with OIR. The authors propose that HIF-2 alpha is a master regulator of proangiogenic factors in retinal vascular endothelial cells, the predominant cell type of the retina in which HIF-2 alpha is expressed. Future studies will address whether the molecular and functional roles for HIF-2 alpha identified from these studies can be generalized to other pathophysiological states involving neovascularization.