title: Functional characterization of Klippel-Trenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis.
abstract: Specification of arteries and veins is a key process for establishing functional vasculature during embryogenesis and involves distinctly different signaling mechanisms. Vascular endothelial growth factor-A (VEGFA) is required for differentiation of arteries; however, the upstream angiogenic factor for vein specification is unknown. Klippel-Trenaunay syndrome (KTS) is a congenital vascular disease associated with capillary and venous malformations (VMs), but not with arterial defects. We have previously reported that upregulation of angiogenic factor AGGF1 is associated with KTS, but the molecular mechanism is not clear. Here, we show that AGGF1 is involved in establishing venous identity in zebrafish embryos. Overexpression of AGGF1 led to increased angiogenesis and increased lumen diameter of veins, whereas knockdown of AGGF1 expression resulted in defective vasculogenesis and angiogenesis. Overexpression of AGGF1 increased expression of venous markers (e.g. flt4), but had little effect on arterial markers (e.g. notch5). Knockdown of AGGF1 expression resulted in a loss of venous identity (loss of expression of flt4, ephb4 and dab2), but had no effect on the expression of arterial development. We further show that AGGF1 activates AKT, and that decreased AGGF1 expression inhibits AKT activation. Overexpression of constitutively active AKT rescues the loss of venous identity caused by AGGF1 downregulation. Our study establishes AGGF1 as an angiogenic factor with an important role in the specification of vein identity and suggests that AGGF1-mediated AKT signaling is responsible for establishing venous cell fate. We propose that increased AGGF1 expression leads to increased vein differentiation by inducing activation of AKT signaling, resulting in VMs s in KTS patients.
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Wuhan, PR China.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yin
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007715:Klippel-Trenaunay-Weber Syndrome / Q000235:genetics* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics* / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D014680:Veins / Q000002:abnormalities / Q000254:growth & development* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: C482200:AGGF1 protein, human; D042501:Angiogenic Proteins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D040321:Vascular Endothelial Growth Factor Receptor-3; D051058:Oncogene Protein v-akt