Hooper Andrea T, Shmelkov Sergey V, Gupta Sunny, Milde Till, Bambino Kathryn, Gillen Kelly, Goetz Mollie, Chavala Sai, Baljevic Muhamed, Murphy Andrew J, Valenzuela David M, Gale Nicholas W, Thurston Gavin, Yancopoulos George D, Vahdat Linda, Evans Todd, Rafii Shahin
Howard Hughes Medical Institute, Weill Cornell Medical College, 1300 York Ave, Room A-863, New York, NY 10021, USA.
Circ Res. 2009 Jul 17;105(2):201-8. doi: 10.1161/CIRCRESAHA.109.196790. Epub 2009 Jun 18.
Blood vessel formation is controlled by the balance between pro- and antiangiogenic pathways. Although much is known about the factors that drive sprouting of neovessels, the factors that stabilize and pattern neovessels are undefined. The expression of angiomodulin (AGM), a vascular endothelial growth factor (VEGF)-A binding protein, was increased in the vasculature of several human tumors as compared to normal tissue, raising the hypothesis that AGM may modulate VEGF-A-dependent vascular patterning. To elucidate the expression pattern of AGM, we developed an AGM knockin reporter mouse (AGM(lacZ/+)), with which we demonstrate that AGM is predominantly expressed in the vasculature of developing embryos and adult organs. During physiological and pathological angiogenesis, AGM is upregulated in the angiogenic vasculature. Using the zebrafish model, we found that AGM is restricted to developing vasculature by 17 to 22 hours postfertilization. Blockade of AGM activity with morpholino oligomers results in prominent angiogenesis defects in vascular sprouting and remodeling. Concurrent knockdown of both AGM and VEGF-A results in synergistic angiogenesis defects. When VEGF-A is overexpressed, the compensatory induction of the VEGF-A receptor, VEGFR2/flk-1, is blocked by the simultaneous injection of AGM morpholino oligomers. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the proangiogenic effects of VEGF-A.
血管生成由促血管生成和抗血管生成途径之间的平衡所控制。尽管我们对驱动新血管芽生的因素已经了解很多，但稳定血管并使其形成特定模式的因素仍不明确。血管调节蛋白（AGM）是一种血管内皮生长因子（VEGF）-A结合蛋白，与正常组织相比，其在几种人类肿瘤的脉管系统中的表达增加，这引发了AGM可能调节VEGF-A依赖性血管模式形成的假说。为了阐明AGM的表达模式，我们构建了一种AGM基因敲入报告小鼠（AGM(lacZ/+)），通过它我们证明AGM主要在发育中的胚胎和成体器官的脉管系统中表达。在生理性和病理性血管生成过程中，AGM在血管生成的脉管系统中上调。利用斑马鱼模型，我们发现受精后17至22小时，AGM局限于发育中的脉管系统。用吗啉代寡聚物阻断AGM活性会导致血管芽生和重塑过程中出现明显的血管生成缺陷。同时敲低AGM和VEGF-A会导致协同的血管生成缺陷。当VEGF-A过表达时，同时注射AGM吗啉代寡聚物会阻断VEGF-A受体VEGFR2/flk-1的代偿性诱导。这些结果表明，血管特异性标志物AGM部分通过调节VEGF-A的促血管生成作用来调节血管重塑。
