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The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.ORCID iD: 0000-0002-6191-7176
Mie Univ, Grad Sch Med, Dept Pediat, Tsu, Mie 5148507, Japan.
Uppsala University, Science for Life Laboratory, SciLifeLab.
Mie Univ, Grad Sch Med, Dept Pediat, Tsu, Mie 5148507, Japan;Nagoya Univ, Grad Sch Med, Dept Pediat Dev Pediat, Nagoya, Aichi 4668550, Japan.
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2019 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 12, no 607, article id eaay4430Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2019. Vol. 12, no 607, article id eaay4430
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Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-398565DOI: 10.1126/scisignal.aay4430ISI: 000496799000003PubMedID: 31719172OAI: oai:DiVA.org:uu-398565DiVA, id: diva2:1376355
Funder
Swedish Cancer Society, 100452Swedish Cancer Society, 2016/445EU, European Research Council, 787472Swedish Research Council, 2015-02757Available from: 2019-12-09 Created: 2019-12-09 Last updated: 2019-12-09Bibliographically approved

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Morikawa, MasatoHolmborn, KatarinaVasilaki, EleftheriaLedin, JohanHeldin, Carl-HenrikMiyazono, Kohei

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Morikawa, MasatoHolmborn, KatarinaVasilaki, EleftheriaSawada, HirofumiLedin, JohanHeldin, Carl-HenrikMiyazono, Kohei
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Science for Life Laboratory, SciLifeLabDepartment of Medical Biochemistry and Microbiology
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