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
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
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Klippel-Trenaunay 综合征基因 Aggf1 的单倍体不足通过灭活 PI3K 和 AKT 抑制发育和病理性血管生成，并通过激活 VE-钙粘蛋白破坏血管完整性
DOI：
10.1093/hmg/ddw273
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Wang QK
中科院分区：
文献类型：
--
作者：
Zhang T;Yao Y;Wang J;Li Y;He P;Vinay Pasupuleti;Hu Z;Jia X;Song Q;Tian X;Chen Q;Wang QK
Aggf 1是第一个被发现的Klippel-Trenaunay综合征（KTS）基因，编码一种血管生成因子。然而，Aggf 1的体内通道尚不完全确定。在这里，我们证明，Aggf 1是必不可少的生理血管生成和病理肿瘤血管生成在体内。两个品系的Aggf 1敲除（KO）小鼠表现出特别严重的表型，因为没有观察到纯合胚胎，并且杂合小鼠也表现出胚胎致死性（单倍致死性不足），仅观察到Vegfa和Dll 4。Aggf 1 +/-KO导致卵黄囊和胚胎中的血管生成缺陷。存活的成年杂合子小鼠表现出频繁的出血和血管通透性增加，这是由于VE-钙粘蛋白的磷酸化增加和膜定位减少。AGGF 1抑制VE-钙粘蛋白磷酸化，增加EC和小鼠中的质膜VE-钙粘蛋白，阻断由缺血-再灌注（IR）诱导的血管通透性，恢复受抑制的心脏功能和收缩，减少梗死面积、心脏纤维化和坏死、出血、水肿和与IR相关的巨噬细胞密度。AGGF 1通过激活PI 3 K的p110α催化亚基和p85α调节亚基，进而激活AKT、GSK 3 β和p70 S6 K，促进血管生成。在杂合KO小鼠和分离的KO EC中，AKT活化显著降低，这可以通过外源性AGGF 1来挽救。来自KO小鼠的EC显示减少的毛细血管生成，其被AGGF 1和AKT拯救。在杂合子小鼠中肿瘤生长/血管生成减少，这与p110α、p85α和AKT的活化减少有关。结合最近在p110α（由PIK 3CA编码）中发现的体细胞突变，我们的数据建立了AGGF 1和PIK 3CA（KTS的两个基因）之间的潜在机制联系。
Aggf1is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, thein vivoroles ofAggf1are incompletely defined. Here we demonstrate thatAggf1is essential for both physiological angiogenesis and pathological tumour angiogenesisin vivo. Two lines ofAggf1knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only forVegfaandDll4.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 byPIK3CA), our data establish a potential mechanistic link betweenAGGF1andPIK3CA, the two genes identified for KTS.