Angiomodulin is a specific marker of vasculature and regulates vascular endothelial growth factor-A-dependent neoangiogenesis.
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.
Hooper
Andrea T
AT
Howard Hughes Medical Institute, Weill Cornell Medical College, 1300 York Ave, Room A-863, New York, NY 10021, USA.
Shmelkov
Sergey V
SV
Gupta
Sunny
S
Milde
Till
T
Bambino
Kathryn
K
Gillen
Kelly
K
Goetz
Mollie
M
Chavala
Sai
S
Baljevic
Muhamed
M
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Gale
Nicholas W
NW
Thurston
Gavin
G
Yancopoulos
George D
GD
Vahdat
Linda
L
Evans
Todd
T
Rafii
Shahin
S
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D009025:Morpholines; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; C086009:tumor-derived adhesion factor; D040301:Vascular Endothelial Growth Factor Receptor-2