Journal
SCIENCE SIGNALING
Volume 12, Issue 607, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aay4430
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Funding
- Swedish Cancer Society [100452, 2016/445]
- KAKENHI [22790750, 17H06326]
- Global Center of Excellence Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan
- Takeda Science Foundation
- European Research Council [787472]
- Swedish Research Council [2015-02757]
- Kanae Foundation for Research Abroad
- ITO Genboku and SAGARA Chian Memorial Scholarship
- Naito Foundation
- Grants-in-Aid for Scientific Research [17H06326, 22790750] Funding Source: KAKEN
- Swedish Research Council [2015-02757] Funding Source: Swedish Research Council
- European Research Council (ERC) [787472] Funding Source: European Research Council (ERC)
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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 2 alpha (HIF-2 alpha) and decreased its abundance, leading to reduced induction of HIF-2 alpha 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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