Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of Atoh8 did not cause an arteriovenous malformation-like phenotype, which may arise because of dysregulated Notch signaling. In contrast, Atoh8-deficient mice exhibited a phenotype mimicking PAH, which included increased pulmonary arterial pressure and right ventricular hypertrophy. Moreover, ATOH8 expression was decreased in PAH patient lungs. We showed that in cells, ATOH8 interacted with hypoxia-inducible factor 2α (HIF-2α) and decreased its abundance, leading to reduced induction of HIF-2α target genes in response to hypoxia. Together, these findings suggest that the BMP receptor type II/ALK-1/SMAD/ATOH8 axis may attenuate hypoxic responses in ECs in the pulmonary circulation and may help prevent the development of PAH.

中文翻译：

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ALK-1 / SMAD / ATOH8轴减弱了低氧反应并防止了肺动脉高压的发展。

内皮细胞（EC）中的骨形态发生蛋白（BMP）信号失调与诸如肺动脉高压（PAH）的血管疾病有关。在这里，我们证明了转录因子ATOH8是SMAD1 / 5的直接靶标，并且以依赖BMP但不依赖于Notch（EC中的另一个关键信号通路）的方式被诱导。在斑马鱼和小鼠中，Atoh8的失活并未引起动静脉畸形样表型，这可能是由于Notch信号传导异常引起的。相反，Atoh8缺陷型小鼠表现出模仿PAH的表型，其中包括肺动脉压升高和右心室肥大。此外，PAH患者肺部ATOH8表达降低。我们发现，在细胞中，ATOH8与缺氧诱导因子2α（HIF-2α）相互作用，并降低其丰度，导致缺氧时HIF-2α靶基因的诱导减少。总之，这些发现表明BMP受体II / ALK-1 / SMAD / ATOH8轴可能会减弱肺循环中EC的低氧反应，并可能有助于预防PAH的发展。