Alk1 Signaling Is Required for Directed Endothelial Cell Migration in the Prevention of Arteriovenous Malformations
Year: 2015
Type: article
Abstract: ALK1, a TGF-β type I receptor serine/threonine kinase, is critical for proper vascular development. Heterozygous loss of ALK1 results in the vascular disorder, hereditary hemorrhagic telangiectasia type 2 (HHT2), which is characterized by the development of arteriovenous malformations (AVMs) and affects 1:8000 people worldwide. alk1-/- zebrafish develop embryonic lethal AVMs which form via a two-step mechanism. First, loss of alk1 results in an increase in endothelial cell number in cranial arteries, which results in increased vessel caliber. In the second step, normally transient connections between arteries and veins are maintained as an adaptive mechanism to cope with an increased hemodynamic load. Using zebrafish as a tool to study the AVM formation due to loss of Alk1 signaling, I have found that Alk1 is required for directed arterial endothelial cell migration in opposition to blood flow. Embryos lacking alk1 experience a redistribution of cells, with endothelial cells failing to efficiently migrate against the direction of blood flow and accumulating in more distal regions of alk1-dependent arteries. This altered cellular distribution causes an increase in arterial caliber and consequent retention of downstream arteriovenous connections, resulting in fatal AVMs. Notch and ALK1 have been implicated in arterial specification and loss of function of either pathway causes AVMs. Furthermore, ALK1 can cooperate with Notch to upregulate expression of Notch target genes in cultured endothelial cells. These findings have led to the hypothesis that Notch and ALK1 collaboratively program arterial identity and prevent AVMs. I modulated Notch and Alk1 activities in zebrafish embryos and examined effects on Notch target gene expression and vascular morphology. Results demonstrate that control of Notch targets is context-dependent, with gene-specific and region-specific requirements for Notch and Alk1. Although loss of alk1 increases expression of dll4, which encodes a Notch ligand, and enhanced Notch signaling causes AVMs, AVMs in alk1 mutants could neither be phenocopied by Notch activation nor rescued by Notch inhibition. In conclusion, Alk1 is dispensable for acquisition and maintenance of arterial identity, and perturbations in Notch signaling cannot account or AVM development in alk1 mutants.
Author: Elizabeth R. Rochon
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1436235039