Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.
Animals
Humans
Arteriovenous Malformations
/ metabolism
Cell Movement
/ physiology
Endothelial Cells
/ metabolism
Telangiectasia, Hereditary Hemorrhagic
/ mortality
Vascular Endothelial Growth Factor A
/ metabolism
Vascular Endothelial Growth Factor Receptor-2
/ metabolism
Vascular Malformations
/ metabolism
Mice
arteriovenous malformations
cell movement
telangiectasia, hereditary hemorrhagic
vascular endothelial growth factor A
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
07 09 2021
07 09 2021
Historique:
pubmed:
30
6
2021
medline:
30
12
2021
entrez:
29
6
2021
Statut:
ppublish
Résumé
Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.
Sections du résumé
BACKGROUND
Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the
METHODS
Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous
RESULTS
ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in
CONCLUSIONS
Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.
Identifiants
pubmed: 34182767
doi: 10.1161/CIRCULATIONAHA.120.053047
pmc: PMC8429266
mid: NIHMS1727528
doi:
Substances chimiques
KDR protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor A
0
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
805-822Subventions
Organisme : NEI NIH HHS
ID : P30 EY026878
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY025979
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135582
Pays : United States
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