title: Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia.
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.
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Baeyens
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Larrivée
authors.affiliation: 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.
authors.forename: Roxana
authors.initials: R
authors.lastname: Ola
authors.affiliation: 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.
authors.forename: Brielle
authors.initials: B
authors.lastname: Hayward-Piatkowskyi
authors.affiliation: 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.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.affiliation: 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.
authors.forename: Billy
authors.initials: B
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Ross
authors.affiliation: 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.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Coon
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Min
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Tsarfati
authors.affiliation: 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.
authors.forename: Haibin
authors.initials: H
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.affiliation: 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.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D001165:Arteriovenous Malformations / Q000473:pathology; D001166:Arteriovenous Shunt, Surgical; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D000071063:Endoglin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D018056:Hemorheology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular; D020286:Pericytes / Q000378:metabolism; D012039:Regional Blood Flow; D012160:Retina / Q000473:pathology; D015398:Signal Transduction; D012995:Solubility; D013314:Stress, Mechanical; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000473:pathology*
chemical_list: D019485:Bone Morphogenetic Proteins; D000071063:Endoglin; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II