Degradome Products of the Matricellular Protein CCN1 as Modulators of Pathological Angiogenesis in the Retina
Degradome Products of the Matricellular Protein CCN1 as Modulators of Pathological Angiogenesis in the Retina
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DOI：
10.1074/jbc.m113.475418
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发表时间：
2013-08-09
影响因子：
4.8
通讯作者：
Chaqour, Brahim
中科院分区：
文献类型：
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作者：
Choi, Jinok;Lin, Ann;Chaqour, Brahim
CCN 1是一种参与正常血管发育和组织修复的基质细胞蛋白。CCN 1表现出细胞和环境依赖性的活动，这反映了其四模块结构与各种基质蛋白中发现的四个结构域在遗传学上相关。在这里，我们表明，增生性糖尿病视网膜病变（PDR）患者的玻璃体液富含CCN 1的两个模块的形式，包括完全或部分的胰岛素样生长因子结合蛋白（IGFBP）和血管性血友病因子C型（vWC）域。除了IGFBP和vWC之外，还包含1型血小板反应蛋白（TSP 1）重复序列的两模块和三模块形式是基质金属蛋白酶-2和-14的CCN 1降解产物。在氧诱导的视网膜病变小鼠模型中确定CCN 1及其截短变体的功能意义，该模型模拟与PDR相关的新生血管生长并评估治疗结果。在该模型中，慢病毒介导的CCN 1或IGFBP-vWC-TSP 1形式的表达减少了缺血诱导的新血管形成，而IGFBP-vWC变体的异位表达加剧了病理性血管生成。IGFBP-vWC形式具有促进视网膜内皮细胞生长、迁移和三维管状结构形成的有效促血管生成特性，而IGFBP-vWC-TSP 1变体抑制细胞生长和血管生成基因表达。IGFBP-vWC和IGFBP-vWC-TSP 1形式均表现出增强其功能潜力的结构域折叠的可预测变化。这些数据为CCN 1截短变体的形成和活性提供了新的见解，并提高了完全或部分含有IGFBP和vWC结构域的形式作为区分病理性和生理性血管生成的PDR中CCN 1活性的替代标志物的预测价值。
CCN1 is a matricellular protein involved in normal vascular development and tissue repair. CCN1 exhibits cell-and context-dependent activities that are reflective of its tetramodular structure phylogenetically linked to four domains found in various matrix proteins. Here, we show that vitreal fluids from patients with proliferative diabetic retinopathy (PDR) were enriched with a two-module form of CCN1 comprising completely or partially the insulin-like growth factor-binding protein (IGFBP) and von Willebrand factor type C (vWC) domains. The two-and three-module forms comprising, in addition to IGFBP and vWC, the thrombospondin type 1 (TSP1) repeats are CCN1 degradome products by matrix metalloproteinase-2 and -14. The functional significance of CCN1 and its truncated variants was determined in the mouse model of oxygen-induced retinopathy, which simulates neovascular growth associated with PDR and assesses treatment outcomes. In this model, lentivirus-mediated expression of either CCN1 or the IGFBP-vWC-TSP1 form reduced ischemia-induced neovascularization, whereas ectopic expression of the IGFBP-vWC variant exacerbated pathological angiogenesis. The IGFBP-vWC form has potent proangiogenic properties promoting retinal endothelial cell growth, migration, and three-dimensional tubular structure formation, whereas the IGFBP-vWC-TSP1 variant suppressed cell growth and angiogenic gene expression. Both IGFBP-vWC and IGFBP-vWC-TSP1 forms exhibited predictable variations of their domain folding that enhanced their functional potential. These data provide new insights into the formation and activities of CCN1-truncated variants and raise the predictive value of the form containing completely or partially the IGFBP and vWC domains as a surrogate marker of CCN1 activity in PDR distinguishing pathological from physiological angiogenesis.