Context-specific interactions between Notch and ALK1 cannot explain ALK1-associated arteriovenous malformations

Cardiovasc Res. 2015 Jul 1;107(1):143-52. doi: 10.1093/cvr/cvv148. Epub 2015 May 12.


Aims: Notch and activin receptor-like kinase 1 (ALK1) have been implicated in arterial specification, angiogenic tip/stalk cell differentiation, and development of arteriovenous malformations (AVMs), and ALK1 can cooperate with Notch to up-regulate expression of Notch target genes in cultured endothelial cells. These findings suggest that Notch and ALK1 might collaboratively program arterial identity and prevent AVMs. We therefore sought to investigate the interaction between Notch and Alk1 signalling in the developing vertebrate vasculature.

Methods and results: We modulated Notch and Alk1 activities in zebrafish embryos and examined effects on Notch target gene expression and vascular morphology. Although Alk1 is not necessary for expression of Notch target genes in arterial endothelium, loss of Notch signalling unmasks a role for Alk1 in supporting hey2 and ephrinb2a expression in the dorsal aorta. In contrast, Notch and Alk1 play opposing roles in hey2 expression in cranial arteries and dll4 expression in all arterial endothelium, with Notch inducing and Alk1 repressing these genes. Although alk1 loss increases expression of dll4, AVMs in alk1 mutants could neither be phenocopied by Notch activation nor rescued by Dll4/Notch inhibition.

Conclusion: Control of Notch targets in arterial endothelium is context-dependent, with gene-specific and region-specific requirements for Notch and Alk1. Alk1 is not required for arterial identity, and perturbations in Notch signalling cannot account for alk1 mutant-associated AVMs. These data suggest that AVMs associated with ALK1 mutation are not caused by defective arterial specification or altered Notch signalling.

Keywords: Activin receptor-like kinase 1; Angiogenesis; Arteriovenous malformation; Notch; Zebrafish.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activin Receptors / physiology*
  • Animals
  • Arteriovenous Malformations / etiology*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Brain / metabolism
  • Gene Expression Regulation
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Proteins / genetics
  • Receptors, Notch / physiology*
  • Signal Transduction
  • Zebrafish / genetics
  • Zebrafish / metabolism*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Zebrafish Proteins
  • delta protein
  • hey2 protein, zebrafish
  • Acvrl1 protein, zebrafish
  • Activin Receptors