The Regulatory Roles of Apoptosis-Inducing Factor in the Formation and Regression Processes of Ocular Neovascularization
The Regulatory Roles of Apoptosis-Inducing Factor in the Formation and Regression Processes of Ocular Neovascularization
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DOI：
10.1016/j.ajpath.2012.03.022
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发表时间：
2012-07-01
影响因子：
6
通讯作者：
Miller, Joan W.
中科院分区：
文献类型：
--
作者：
Hisatomi, Toshio;Nakao, Shintaro;Miller, Joan W.
细胞凋亡在新生血管形成和消退中的作用在很大程度上是假说的，尽管具体机制尚不清楚。炎症细胞和内皮细胞在新生血管形成过程中都参与并相互作用。在早期阶段，这些细胞可能迁移到血管生成部位，形成有利于血管生成的微环境。一些新生血管似乎退缩，而一些血管成熟并保持不变。然而，这些过程的控制机制仍不清楚。在此研究中，我们使用两种眼部新生血管模型：激光损伤脉络膜新生血管和血管内皮生长因子诱导的角膜新生血管，研究了细胞凋亡在血管生成中的调节作用。与野生型小鼠相比，避免AIF缺陷小鼠的细胞凋亡减少了白细胞和内皮细胞的凋亡，并导致这些细胞在体外和体内的血管生成部位持续存在。因此，在这两个模型中，AIF缺乏扩大了新生血管，减少了血管退行性变。我们还观察到，在饥饿条件下，与野生型小鼠相比，AIF缺陷小鼠的腹膜巨噬细胞表现出抗凋亡的存活。提示ALF相关的细胞凋亡在新生血管形成中起重要作用，线粒体调控的细胞凋亡可能为病理性血管生成的治疗提供新的靶点。(Am J Pathol2012,181：53-61；http://dx.doi.org/10.1016/j.ajpath.2012.03.022)
The role of apoptosis in the formation and regression of neovascularization is largely hypothesized, although the detailed mechanism remains unclear. Inflammatory cells and endothelial cells both participate and interact during neovascularization. During the early stage, these cells may migrate into an angiogenic site and form a pro-angiogenic microenvironment. Some angiogenic vessels appear to regress, whereas some vessels mature and remain. The control mechanisms of these processes, however, remain unknown. Previously, we reported that the prevention of :mitochondrial apoptosis contributed to cellular survival via the prevention of the release of proapoptotic factors, such as apoptosis-inducing factor (AIF) and cytochrome c. In this study, we investigated the regulatory role of cellular apoptosis in angiogenesis using two models of ocular neovascularization: laser injury choroidal neovascularization and VEGF-induced corneal neovascularization in AIF-deficient mice. Averting apoptosis in AIF-deficient mice decreased apoptosis of leukocytes and endothelial cells compared to wild-type mice and resulted in the persistence of these cells at angiogenic sites in vitro and in vivo. Consequently, AIF deficiency expanded neovascularization and diminished vessel regression in these two models. We also observed that peritoneal macrophages from AIF-deficient mice showed anti-apoptotic survival compared to wild-type mice under conditions of starvation. Our data suggest that ALF-related apoptosis plays an important role in neovascularization and that mitochondria-regulated apoptosis could offer a new target for the treatment of pathological angiogenesis. (Am J Pathol 2012, 181:53-61; http://dx.doi.org/10.1016/j.ajpath.2012.03.022)