Angiomodulin is a specific marker of vasculature and regulates VEGF-A dependent neo-angiogenesis

• Published in: Circulation research 2009-06, Vol.105 (2), p.201-208
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.196790

Blood vessel formation is controlled by the balance between pro- and anti-angiogenic 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 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 /+ ) wherein 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 17-22 hpf. Blockade of AGM activity with morpholino oligomers (MO) 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, VEGFR-2/flk-1, is blocked by the simultaneous injection of AGM MO. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the pro-angiogenic effects of VEGF-A.