Research ArticleVASCULAR BIOLOGY

The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension

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Science Signaling  12 Nov 2019:
Vol. 12, Issue 607, eaay4430
DOI: 10.1126/scisignal.aay4430

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BMP blocks PAH through ATOH8

Defects in the BMP signaling pathway in endothelial cells can lead to pulmonary arterial hypertension (PAH), a condition that can lead to heart failure if prolonged. Morikawa et al. found that BMP signaling promoted the expression of the transcription factor ATOH8. Mice lacking Atoh8 had symptoms reminiscent of PAH, and PAH patient lung samples showed decreased ATOH8 expression. In cells, ATOH8 bound to and decreased the abundance of HIF-2α, a transcription factor that is critical for the cellular response to hypoxia. These results suggest that ATOH8 may counteract hypoxic signaling in endothelial cells and prevent the development of PAH.

Abstract

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.

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