VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.
VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.
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VEGF164介导的炎症是病理学所必需的，但不是生理，缺血诱导的视网膜新血管形成。
DOI：
10.1084/jem.20022027
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发表时间：
2003-08-04
影响因子：
15.3
通讯作者：
Adamis, AP
中科院分区：
文献类型：
--
作者：
Ishida, S;Usui, T;Yamashiro, K;Kaji, Y;Amano, S;Ogura, Y;Hida, T;Oguchi, Y;Ambati, J;Miller, JW;Gragoudas, ES;Ng, YS;D'Amore, PA;Shima, DT;Adamis, AP
缺氧诱导的 VEGF 控制生理性视网膜血管发育和病理性视网膜新生血管形成。本文对生理性和病理性新生血管形成的机制进行了比较和对比。在病理性新生血管形成期间，VEGF164的绝对和相对表达水平均比生理性新生血管形成期间增加更大程度。此外，在病理性而非生理性新血管形成的前沿观察到广泛的白细胞粘附。当施用VEGF164特异性中和适体时，它有效抑制白细胞粘附和病理性新生血管形成，而对生理性新生血管形成影响很小或没有影响。在平行实验中，与野生型 (VEGF+/+) 对照相比，基因改造的 VEGF164 缺陷 (VEGF120/188) 小鼠在生理性新血管形成方面没有表现出差异。相比之下，施用阻断所有 VEGF 同工型的 VEGFR-1/Fc 融合蛋白可显着抑制病理性和生理性新血管形成。此外，用氯膦酸盐脂质体靶向灭活单核细胞谱系细胞可抑制病理性新血管形成。相反，用抗 CD2 抗体阻断 T 淋巴细胞介导的免疫反应会加剧病理性新生血管形成。这些数据强调了生理性和病理性视网膜新生血管形成之间重要的分子和细胞差异。在病理性新生血管形成过程中，VEGF164 选择性诱导炎症和细胞免疫。这些过程分别提供正向和负向血管生成调节。总之，概述了选择性针对病理性而非生理性视网膜新生血管形成的新治疗方法。
Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte–mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.
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