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

Research output: Contribution to journalArticle

Authors

  • Teresa L. Capasso
  • Bijun Li
  • Harry J. Volek
  • Waqas Khalid
  • Elizabeth R. Rochon
  • Arulselvi Anbalagan
  • Chelsea Herdman
  • H. Joseph Yost
  • Flordeliza S. Villanueva
  • Kang Kim
  • Beth L. Roman

External Institution(s)

  • University of Pittsburgh
  • University of Utah

Details

Original languageEnglish (US)
Pages (from-to)203-220
Number of pages18
JournalAngiogenesis
Volume23
Issue number2
StatusPublished - May 1 2020
Peer-reviewedYes

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.

    Research areas

  • Bone morphogenetic protein, Hereditary hemorrhagic telangiectasia, Vascular development, Zebrafish

Citation formats

APA

Capasso, T. L., Li, B., Volek, H. J., Khalid, W., Rochon, E. R., Anbalagan, A., ... Roman, B. L. (2020). BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance. Angiogenesis, 23(2), 203-220. https://doi.org/10.1007/s10456-019-09701-0

Harvard

Capasso, TL, Li, B, Volek, HJ, Khalid, W, Rochon, ER, Anbalagan, A, Herdman, C, Yost, HJ, Villanueva, FS, Kim, K & Roman, BL 2020, 'BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance', Angiogenesis, vol. 23, no. 2, pp. 203-220. https://doi.org/10.1007/s10456-019-09701-0