BACKGROUND: Response gene to complement 32 (RGC-32) is induced by activation of complement and regulates cell proliferation. To determine the mechanism of RGC-32 in angiogenesis, we examined the role of RGC-32 in hypoxia-related endothelial cell function. METHODS AND RESULTS: Hypoxia/ischemia is able to stimulate both angiogenesis and apoptosis. Hypoxia-inducible factor-1/vascular endothelial growth factor is a key transcriptional regulatory pathway for angiogenesis during hypoxia. We demonstrated that the increased RGC-32 expression by hypoxia was via hypoxia-inducible factor-1/vascular endothelial growth factor induction in cultured endothelial cells. However, overexpression of RGC-32 reduced the proliferation and migration and destabilized vascular structure formation in vitro and inhibited angiogenesis in Matrigel assays in vivo. Silencing RGC-32 had an opposing, stimulatory effect. RGC-32 also stimulated apoptosis as shown by the increased apoptotic cells and caspase-3 cleavage. Mechanistic studies revealed that the effect of RGC-32 on the antiangiogenic response was via attenuating fibroblast growth factor 2 expression and further inhibiting expression of cyclin E without affecting vascular endothelial growth factor and fibroblast growth factor 2 signaling in endothelial cells. In the mouse hind-limb ischemia model, RGC-32 inhibited capillary density with a significant attenuation in blood flow. Additionally, treatment with RGC-32 in the xenograft tumor model resulted in reduced growth of blood vessels that is consistent with reduced colon tumor size. CONCLUSIONS: We provide the first direct evidence for RGC-32 as a hypoxia-inducible gene and antiangiogenic factor in endothelial cells. These data suggest that RGC-32 plays an important homeostatic role in that it contributes to differentiating the pathways for vascular endothelial growth factor and fibroblast growth factor 2 in angiogenesis and provides a new target for ischemic disorder and tumor therapies.
BACKGROUND:Response gene to complement 32 (RGC-32) is induced by activation of complement and regulates cell proliferation. To determine the mechanism of RGC-32 in angiogenesis, we examined the role of RGC-32 in hypoxia-related endothelial cell function. METHODS AND RESULTS:Hypoxia/ischemia is able to stimulate both angiogenesis and apoptosis. Hypoxia-inducible factor-1/vascular endothelial growth factor is a key transcriptional regulatory pathway for angiogenesis during hypoxia. We demonstrated that the increased RGC-32 expression by hypoxia was via hypoxia-inducible factor-1/vascular endothelial growth factor induction in cultured endothelial cells. However, overexpression of RGC-32 reduced the proliferation and migration and destabilized vascular structure formation in vitro and inhibited angiogenesis in Matrigel assays in vivo. Silencing RGC-32 had an opposing, stimulatory effect. RGC-32 also stimulated apoptosis as shown by the increased apoptotic cells and caspase-3 cleavage. Mechanistic studies revealed that the effect of RGC-32 on the antiangiogenic response was via attenuating fibroblast growth factor 2 expression and further inhibiting expression of cyclin E without affecting vascular endothelial growth factor and fibroblast growth factor 2 signaling in endothelial cells. In the mouse hind-limb ischemia model, RGC-32 inhibited capillary density with a significant attenuation in blood flow. Additionally, treatment with RGC-32 in the xenograft tumor model resulted in reduced growth of blood vessels that is consistent with reduced colon tumor size. CONCLUSIONS: We provide the first direct evidence for RGC-32 as a hypoxia-inducible gene and antiangiogenic factor in endothelial cells. These data suggest that RGC-32 plays an important homeostatic role in that it contributes to differentiating the pathways for vascular endothelial growth factor and fibroblast growth factor 2 in angiogenesis and provides a new target for ischemic disorder and tumor therapies.
Authors: Christie Barclay; Audrey W Li; Laurette Geldenhuys; Mark Baguma-Nibasheka; Geoffrey A Porter; Paul J Veugelers; Paul R Murphy; Alan G Casson Journal: Clin Cancer Res Date: 2005-11-01 Impact factor: 12.531
Authors: I B Lobov; R A Renard; N Papadopoulos; N W Gale; G Thurston; G D Yancopoulos; S J Wiegand Journal: Proc Natl Acad Sci U S A Date: 2007-02-12 Impact factor: 11.205
Authors: Huiyan Zeng; Liuliang Qin; Dezheng Zhao; Xiaolian Tan; Eleanor J Manseau; Mien Van Hoang; Donald R Senger; Lawrence F Brown; Janice A Nagy; Harold F Dvorak Journal: J Exp Med Date: 2006-03-06 Impact factor: 14.307
Authors: Sonia I Vlaicu; Alexandru Tatomir; Violeta Rus; Armugam P Mekala; Petru A Mircea; Florin Niculescu; Horea Rus Journal: Immunol Res Date: 2016-02 Impact factor: 2.829
Authors: Sonia I Vlaicu; Cosmin A Tegla; Cornelia D Cudrici; Jacob Danoff; Hassan Madani; Adam Sugarman; Florin Niculescu; Petru A Mircea; Violeta Rus; Horea Rus Journal: Immunol Res Date: 2013-05 Impact factor: 2.829