Abstract 3665: Aggf1 Is Essential for Embryonic and Pathological Angiogenesis

Abstract

Backgroud: AGGF1 is a newly identified angiogenic factor associated with vascular disease Klippel-Trenaunay syndrome. AGGF1 has been shown to promote angiogenesis as potently as VEGF in a chicken embryo angiogenesis assay; however, the physiological role of AGGF1 is unknown. Methods and Results: We explored the physiological function of AGGF1 in vivo by employing the gene-trapping strategy in mice. AGGF1−/− mice died by E8.5, suggesting that AGGF1 is essential for embryogenesis. AGGF1 heterozygosity resulted in 31% embryonic lethality. Further macroscopic analysis of embryos at different stages revealed growth retardation and defective vascular development in AGGF1+/− embryos. The major vascular phenotypes included failed development of large vessels and interconnected yolk sac vasculature. Interestingly, decreased phosphorylation of VEGFR2 (Tyr951) was detected in AGGF1+/− embryos compared to the wild type littermate controls, suggesting that AGGF1 may function through VEGFR2-mediated signaling during angiogenesis. Moreover, vascular pathologies of various internal organs were detected in older AGGF1+/− mice. Hemorrhages were frequently noted in brain, spleen and lung, and a chronic inflammatory change was readily detected in lungs in AGGF1+/− mice compared to the littermate controls. Permeability assay further revealed increased vascular permeability in old AGGF1+/− mice (50 – 60 weeks) compared to age- and sex-matched wild-type controls. A tumor angiogenesis model induced by two melanoma cell lines was employed to further assess the angiogenic function of AGGF1 in vivo. Tumor growth was significantly inhibited in AGGF1+/− mice. Histological examinations of the tumor sections revealed markedly reduced microvessel formation in tumors grown in AGGF1+/− mice. Moreover, vascular density quantified after PECAM1 immunostaining showed significant reduction in tumors grown in AGGF1+/− mice. Conclusions: AGGF1 is an important regulator for embryonic angiogenesis and vascular integrity. AGGF1 is also involved in tumor growth and pathological angiogenesis. These results provide for the first time the in vivo experimental evidence that AGGF1 is a potent angiogenic factor essential for both embryonic and pathological angiogenesis.