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Aggf1  is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the  in vivo  roles of  Aggf1  are incompletely defined. Here we demonstrate that  Aggf1  is essential for both physiological angiogenesis and pathological tumour angiogenesis  in vivo . Two lines of  Aggf1  knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for  Vegfa  and  Dll4 .  Aggf1 +/−   KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3β and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by  PIK3CA ), our data establish a potential mechanistic link between  AGGF1  and  PIK3CA , the two genes identified for KTS.

human molecular genetics

Haploinsufficiency of Klippel-Trenaunay syndrome gene  Aggf1  inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin