Arhgef15 promotes retinal angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells.
Arhgef15 promotes retinal angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells.
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DOI：
10.1371/journal.pone.0045858
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Uemura A
中科院分区：
文献类型：
--
作者：
Kusuhara S;Fukushima Y;Fukuhara S;Jakt LM;Okada M;Shimizu Y;Hata M;Nishida K;Negi A;Hirashima M;Mochizuki N;Nishikawa S;Uemura A
抑制血管内皮生长因子(VEGF)信号转导的药物在全球范围内被用来抑制各种眼病中放松调控的血管生成。然而，抗血管内皮生长因子治疗可能会影响视网膜神经元和神经胶质细胞的正常功能，而视网膜神经元和神经胶质细胞构成了表达血管内皮生长因子受体2的基础。因此，寻找仅在血管内皮细胞(ECs)中表达的新型药物靶点是非常必要的。在此，我们试图鉴定一种EC特异性的Rho鸟嘌呤核苷酸交换因子，并评估其在视网膜血管生成中的作用。通过利用荧光激活的细胞分选和微阵列分析，结合电子生物信息学分析，我们全面地鉴定了出生后小鼠视网膜血管新生血管中的内皮基因。在9种在视网膜内皮细胞中高表达的RhoGEF中，我们发现Arhgef15作为一种EC特异性的环境生长因子，介导了血管内皮生长因子诱导的CDC42的激活并增强了RhoJ的失活，从而促进了肌动蛋白的聚合和细胞的运动。Arhgef15基因的破坏导致出生后小鼠视网膜血管网络延迟延伸，随后血管总面积减少。我们的研究为开发选择性地操作血管生成而不影响非靶向组织的动态平衡的新方法提供了有用的信息；不仅在眼睛中，而且在各种疾病环境中，如癌症。
Drugs inhibiting vascular endothelial growth factor (VEGF) signaling are globally administered to suppress deregulated angiogenesis in a variety of eye diseases. However, anti-VEGF therapy potentially affects the normal functions of retinal neurons and glias which constitutively express VEGF receptor 2. Thus, it is desirable to identify novel drug targets which are exclusively expressed in endothelial cells (ECs). Here we attempted to identify an EC-specific Rho guanine nucleotide exchange factor (GEF) and evaluate its role in retinal angiogenesis. By exploiting fluorescence-activated cell sorting and microarray analyses in conjunction with in silico bioinformatics analyses, we comprehensively identified endothelial genes in angiogenic retinal vessels of postnatal mice. Of 9 RhoGEFs which were highly expressed in retinal ECs, we show that Arhgef15 acted as an EC-specific GEF to mediate VEGF-induced Cdc42 activation and potentiated RhoJ inactivation, thereby promoting actin polymerization and cell motility. Disruption of the Arhgef15 gene led to delayed extension of vascular networks and subsequent reduction of total vessel areas in postnatal mouse retinas. Our study provides information useful to the development of new means of selectively manipulating angiogenesis without affecting homeostasis in un-targeted tissues; not only in eyes but also in various disease settings such as cancer.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
3.7
作者：
Saint-Geniez M;Maharaj AS;Walshe TE;Tucker BA;Sekiyama E;Kurihara T;Darland DC;Young MJ;D'Amore PA
通讯作者：
D'Amore PA
影响因子：
2.7
作者：
Takebe, A;Era, T;Nishikawa, SI
通讯作者：
Nishikawa, SI
影响因子：
158.5
作者：
Rosenfeld, Philip J.;Brown, David M.;Kim, Robert Y.
通讯作者：
Kim, Robert Y.
影响因子：
4.6
作者：
Sato, Takahiro;Kawamura, Yumiko;Kurihara, Hiroki
通讯作者：
Kurihara, Hiroki