Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
PLoS One. 2012;7(12):e51647. doi: 10.1371/journal.pone.0051647. Epub 2012 Dec 18.
Human CD93, an epidermal growth factor (EGF)-like domain containing transmembrane protein, is predominantly expressed in the vascular endothelium. Studies have shown that AA4, the homolog of CD93 in mice, may mediate cell migration and angiogenesis in endothelial cells. Soluble CD93 has been detected in the plasma of healthy individuals. However, the role of soluble CD93 in the endothelium remains unclear. Recombinant soluble CD93 proteins with EGF-like domains (rCD93D123, with domains 1, 2, and 3; and rCD93D23, with domains 2 and 3) were generated to determine their functions in angiogenesis. We found that rCD93D23 was more potent than rCD93D123 in stimulating the proliferation and migration of human umbilical vein endothelial cells (HUVECs). Production of matrix-metalloproteinase 2 increased after the HUVECs were treated with rCD93D23. Further, in a tube formation assay, rCD93D23 induced cell differentiation of HUVECs through phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase and extracellular signal-regulated kinases-1/2 signaling. Moreover, rCD93D23 promoted blood vessel formation in a Matrigel-plug assay and an oxygen-induced retinopathy model in vivo. Our findings suggest that the soluble EGF-like domain containing CD93 protein is a novel angiogenic factor acting on the endothelium.
人 CD93，一种含有表皮生长因子 (EGF)样结构域的跨膜蛋白，主要在血管内皮细胞中表达。研究表明，小鼠 CD93 的同源物 AA4 可能介导内皮细胞中的细胞迁移和血管生成。可溶性 CD93 已在健康个体的血浆中检测到。然而，可溶性 CD93 在血管内皮中的作用尚不清楚。为了确定其在血管生成中的功能，我们生成了具有 EGF 样结构域的重组可溶性 CD93 蛋白（rCD93D123，包含结构域 1、2 和 3；和 rCD93D23，包含结构域 2 和 3）。我们发现 rCD93D23 比 rCD93D123 更能刺激人脐静脉内皮细胞 (HUVEC) 的增殖和迁移。rCD93D23 处理 HUVEC 后，基质金属蛋白酶 2 的产生增加。此外，在管形成测定中，rCD93D23 通过磷酸肌醇 3-激酶/Akt/内皮型一氧化氮合酶和细胞外信号调节激酶 1/2 信号通路诱导 HUVEC 细胞分化。此外，rCD93D23 在 Matrigel 塞子测定和体内氧诱导的视网膜病变模型中促进血管形成。我们的研究结果表明，可溶性含有 EGF 样结构域的 CD93 蛋白是一种作用于内皮细胞的新型血管生成因子。
