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

转化生长因子β超家族的成员在胚胎发育和生理器官功能的各个方面发挥着重要作用。其中骨形态发生蛋白（BMP） 9和BMP10通过激活其内皮受体ALK1调控胚胎血管发育。alk1介导的细胞内信号与HHT和肺动脉高压等人类疾病的病因有关，但其下游功能蛋白在很大程度上是未知的。我们发现基因X是一个胚胎内皮富集基因，通过ALK1受体被BMP9和BMP10激活。基因X缺失小鼠由于动脉内皮分化受损和血管形态发生缺陷而表现出胚胎致死性。notch和akt介导的信号通路对血管发育至关重要，但在基因X缺失的小鼠中，这些信号通路的活性被下调，这表明基因X缺乏至少在一定程度上通过这些信号通路的失调导致血管死亡。这些数据表明，在内皮分化和血管形态发生过程中，基因X在BMP9/BMP10-ALK1信号的下游发挥着不可或缺的作用。ACVRL1/ALK1和BMPR2突变可导致人类遗传性出血性毛细血管扩张和肺动脉高压。基因X可能作为额外的致病基因或修饰因子参与这些疾病的机制。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，在非应激条件下，cKO小鼠不会自发发生肺动脉高压。我们正在研究缺氧是否会引起cKO小鼠的严重肺动脉高压。

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.