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(Circulation Research. 2009;105:201.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Angiomodulin Is a Specific Marker of Vasculature and Regulates Vascular Endothelial Growth Factor-A–Dependent Neoangiogenesis

Andrea T. Hooper, Sergey V. Shmelkov, Sunny Gupta, Till Milde, Kathryn Bambino, Kelly Gillen, Mollie Goetz, Sai Chavala, Muhamed Baljevic, Andrew J. Murphy, David M. Valenzuela, Nicholas W. Gale, Gavin Thurston, George D. Yancopoulos, Linda Vahdat, Todd Evans, Shahin Rafii

From the Howard Hughes Medical Institute, Department of Genetic Medicine, Ansary Stem Cell Institute (A.T.H., S.V.S., T.M., K.B., K.G., M.G., S.C., M.B., S.R.) and Department of Medicine (L.V.), Weill Cornell Medical College, New York; Department of Developmental & Molecular Biology (S.G., T.E.), Albert Einstein College of Medicine, Bronx, NY; and Regeneron Pharmaceuticals (A.J.M., D.M.V., N.W.G., G.T., G.D.Y.), Tarrytown, NY. Present address for T.E.: Department of Surgery, Weill Cornell Medical College, New York.

Correspondence to Shahin Rafii, MD, Howard Hughes Medical Institute, Weill Cornell Medical College, 1300 York Ave, Room A-863, New York, NY 10021. E-mail srafii{at}med.cornell.edu

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.

Key Words: angiomodulin • IGFBP-7 • angiogenesis • VEGF • zebrafish