Identifying a novel gene contributing to vascular maturation and its significance in cardiovascular diseases.

转化生长因子β超家族成员在胚胎发育和生理器官功能的各个方面发挥着重要的作用。其中，骨形态发生蛋白9和骨形态发生蛋白10通过激活其内皮细胞受体ALK1来调节胚胎血管的发育。ALK1介导的细胞内信号转导与高血压、肺动脉高压等人类疾病的发生密切相关，但其下游功能蛋白在很大程度上尚不清楚。我们发现X基因是一个由BMP9和BMP10通过ALK1受体激活的胚胎内皮增强型基因。X基因缺失小鼠由于动脉内皮细胞分化障碍和血管形态发生缺陷而表现出胚胎致死性。在X基因缺失的小鼠中，Notch和Akt介导的对血管发育至关重要的信号通路的活性被下调，这表明X基因缺失导致血管死亡，至少部分是通过这些信号通路的失调。这些数据表明，X基因在BMP9/BMP10-ALK1信号下游的内皮分化和血管形态形成过程中起着不可或缺的作用。ACVRL1/ALK1和BMPR2基因突变导致人类遗传性出血性毛细血管扩张和肺动脉高压。X基因可能作为额外的致病基因或修饰物参与了这些疾病的发病机制。为了证明这一假设，我们分析了他莫昔芬诱导X基因失活的条件性KO小鼠。然而，CKO小鼠在非应激条件下不会自发发展为肺动脉高压。我们正在研究低氧是否会导致CKO小鼠出现严重的肺动脉高压。

Members of the transforming growth factorβsuperfamily play essential roles in various aspects of embryonic development and physiological organ function. Among them, bone morphogenetic protein(BMP) 9 and BMP10 regulate embryonic vascular development by activating their endothelial receptor ALK1.ALK1-mediated intracellular signaling is implicated in the etiologies of human diseases such as HHT and pulmonary hypertension, but their downstream functional proteins are largely unknown. We identified gene X to be an embryonic endothelium-enriched gene activated by BMP9 and BMP10 through the ALK1 receptor. Gene X null mice showed embryonic lethality due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis. The activity of Notch-and Akt-mediated signaling, which is essential for vascular development, was down regulated in gene X null mice, suggesting that the gene X deficiency leads to vascular demise, at least in part, through dysregulation of these signaling pathways. These data indicated that gene X play indispensable roles downstream of BMP9/BMP10-ALK1 signaling during endothelial differentiation and vascular morphogenesis.Mutations in ACVRL1/ALK1 and BMPR2 cause hereditary hemorrhagic telangiectasia as well as pulmonary arterial hypertension in humans. Gene X might be involved in the mechanisms of these diseases as an additional causative gene or a modifier. To demonstrate this hypothesis we analyzed conditional KO mice of tamoxifen-induced inactivation of gene X. However cKO mice did not develop pulmonary hypertension spontaneously under unstressed conditions. We are investigating whether hypoxia induced severe pulmonary hypertension in cKO mice.