PUBLICATION

Interaction between alk1 and blood flow in the development of arteriovenous malformations

Authors
Corti, P., Young, S., Chen, C.Y., Patrick, M.J., Rochon, E.R., Pekkan, K., and Roman, B.L.
ID
ZDB-PUB-110325-2
Date
2011
Source
Development (Cambridge, England)   138(8): 1573-1582 (Journal)
Registered Authors
Roman, Beth, Young, Sarah
Keywords
Arteriovenous malformation, Alk1/Acvrl1, Hereditary hemorrhagic telengiectasia, Zebrafish
MeSH Terms
  • Activin Receptors, Type I/genetics
  • Activin Receptors, Type I/metabolism*
  • Animals
  • Arteriovenous Malformations/etiology
  • Arteriovenous Malformations/metabolism*
  • Blood Flow Velocity/physiology*
  • Embryo, Nonmammalian
  • In Situ Hybridization, Fluorescence
  • Telangiectasia, Hereditary Hemorrhagic/etiology
  • Telangiectasia, Hereditary Hemorrhagic/metabolism
  • Zebrafish
PubMed
21389051 Full text @ Development
Abstract
Arteriovenous malformations (AVMs) are fragile direct connections between arteries and veins that arise during times of active angiogenesis. To understand the etiology of AVMs and the role of blood flow in their development, we analyzed AVM development in zebrafish embryos harboring a mutation in activin receptor-like kinase I (alk1), which encodes a TGFβ family type I receptor implicated in the human vascular disorder hereditary hemorrhagic telangiectasia type 2 (HHT2). Our analyses demonstrate that increases in arterial caliber, which stem in part from increased cell number and in part from decreased cell density, precede AVM development, and that AVMs represent enlargement and stabilization of normally transient arteriovenous connections. Whereas initial increases in endothelial cell number are independent of blood flow, later increases, as well as AVMs, are dependent on flow. Furthermore, we demonstrate that alk1 expression requires blood flow, and despite normal levels of shear stress, some flow-responsive genes are dysregulated in alk1 mutant arterial endothelial cells. Taken together, our results suggest that Alk1 plays a role in transducing hemodynamic forces into a biochemical signal required to limit nascent vessel caliber, and support a novel two-step model for HHT-associated AVM development in which pathological arterial enlargement and consequent altered blood flow precipitate a flow-dependent adaptive response involving retention of normally transient arteriovenous connections, thereby generating AVMs.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping