Format

Send to

Choose Destination
Sci Signal. 2019 Nov 12;12(607). pii: eaay4430. doi: 10.1126/scisignal.aay4430.

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

Author information

1
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
2
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-751 23 Uppsala, Sweden.
3
Ludwig Institute for Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
4
Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
5
Genome Engineering Zebrafish Facility, Science For Life Laboratory, Uppsala University, SE-752 36 Uppsala, Sweden.
6
Department of Anesthesiology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
7
Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
8
Department of Medical Joint Materials, Kagoshima University, Kagoshima, Kagoshima 890-8544, Japan.
9
Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan.
10
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-751 23 Uppsala, Sweden. c-h.heldin@imbim.uu.se miyazono@m.u-tokyo.ac.jp.
11
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. c-h.heldin@imbim.uu.se miyazono@m.u-tokyo.ac.jp.

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.

PMID:
31719172
DOI:
10.1126/scisignal.aay4430

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center