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J Cell Biol. 2016 Sep 26;214(7):807-16. doi: 10.1083/jcb.201603106. Epub 2016 Sep 19.

Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia.

Author information

1
Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511 Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511.
2
Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511 Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511 Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
3
Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511 Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511 Jilin Provincial Key Laboratory of Molecular Geriatric Medicine, Life Science Research Center, Beihua University, Jilin 132013, China.
4
Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511 Institut National de la Santé et de la Recherche Médicale U970, Paris Center for Cardiovascular Research, 75015 Paris, France.
5
Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511 Department of Cell Biology, Yale University, New Haven, CT 06510 Department of Biomedical Engineering, Yale University, New Haven, CT 06510 martin.schwartz@yale.edu.

Abstract

Morphogenesis of the vascular system is strongly modulated by mechanical forces from blood flow. Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal-dominant disease in which arteriovenous malformations and telangiectasias accumulate with age. Most cases are linked to heterozygous mutations in Alk1 or Endoglin, receptors for bone morphogenetic proteins (BMPs) 9 and 10. Evidence suggests that a second hit results in clonal expansion of endothelial cells to form lesions with poor mural cell coverage that spontaneously rupture and bleed. We now report that fluid shear stress potentiates BMPs to activate Alk1 signaling, which correlates with enhanced association of Alk1 and endoglin. Alk1 is required for BMP9 and flow responses, whereas endoglin is only required for enhancement by flow. This pathway mediates both inhibition of endothelial proliferation and recruitment of mural cells; thus, its loss blocks flow-induced vascular stabilization. Identification of Alk1 signaling as a convergence point for flow and soluble ligands provides a molecular mechanism for development of HHT lesions.

PMID:
27646277
PMCID:
PMC5037412
DOI:
10.1083/jcb.201603106
[Indexed for MEDLINE]
Free PMC Article

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