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BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance

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Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder characterized by development of high-flow arteriovenous malformations (AVMs) that can lead to stroke or high-output heart failure. HHT2 is caused by heterozygous mutations in ACVRL1, which encodes an endothelial cell bone morphogenetic protein (BMP) receptor, ALK1. BMP9 and BMP10 are established ALK1 ligands. However, the unique and overlapping roles of these ligands remain poorly understood. To define the physiologically relevant ALK1 ligand(s) required for vascular development and maintenance, we generated zebrafish harboring mutations in bmp9 and duplicate BMP10 paralogs, bmp10 and bmp10-like. bmp9 mutants survive to adulthood with no overt phenotype. In contrast, combined loss of bmp10 and bmp10-like results in embryonic lethal cranial AVMs indistinguishable from acvrl1 mutants. However, despite embryonic functional redundancy of bmp10 and bmp10-like, bmp10 encodes the only required Alk1 ligand in the juvenile-to-adult period. bmp10 mutants exhibit blood vessel abnormalities in anterior skin and liver, heart dysmorphology, and premature death, and vascular defects correlate with increased cardiac output. Together, our findings support a unique role for Bmp10 as a non-redundant Alk1 ligand required to maintain the post-embryonic vasculature and establish zebrafish bmp10 mutants as a model for AVM-associated high-output heart failure, which is an increasingly recognized complication of severe liver involvement in HHT2.

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Acknowledgements

We thank J. Keith Joung (Massachusetts General Hospital) for generating TALENs (NIH R01GM088040); the Sanger Institute Zebrafish Mutation Project, Sarah Childs (University of Calgary), Ching-Ling Lien (University of Southern California), Stephan Schulte-Merker (University of Münster), and Deborah Yelon (University of California-San Diego) for providing fish lines; Su Diler for technical assistance; Brenda Diergaarde (University of Pittsburgh) for statistical help; and Rachael Gerheart, Yahya Lodi, and Pitt aquatics staff for fish care.

Funding

This work was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH), R01HL133009 (BR), R01HL136566 (BR), and UM1HL098160 (HJY), and the Institute for Transfusion Medicine/Vitalant (BLR). The Vevo2100 small animal imaging system was funded by NIH 1S10RR027383-01 (KK).

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Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Teresa L. Capasso, Bijun Li, Elizabeth R. Rochon, Arulselvi Anbalagan & Beth L. Roman

  2. Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Harry J. Volek, Waqas Khalid & Kang Kim

  3. Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Elizabeth R. Rochon, Flordeliza S. Villanueva, Kang Kim & Beth L. Roman

  4. Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA

    Chelsea Herdman & H. Joseph Yost

  5. Center for Ultrasound Molecular Imaging and Therapeutics, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Flordeliza S. Villanueva & Kang Kim

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  1. Teresa L. Capasso
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Contributions

BLR designed the research, generated mutants, and wrote the manuscript. TLC contributed to research design, performed experiments, analyzed data, and contributed to manuscript preparation. BL performed adult heart analysis and coordinated and summarized ultrasound imaging experiments. HJV, WK, FSV, and KK performed ultrasound imaging and data analysis. ERR and AA provided technical assistance. CH and HJY analyzed single cell RNAseq data. All authors contributed to final editing and approval of the manuscript.

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Correspondence to Beth L. Roman.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Pittsburgh (PHS approval A3187-01).

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Capasso, T.L., Li, B., Volek, H.J. et al. BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance. Angiogenesis 23, 203–220 (2020). https://doi.org/10.1007/s10456-019-09701-0

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