期刊
CIRCULATION
卷 144, 期 10, 页码 805-822出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.120.053047
关键词
arteriovenous malformations; cell movement; telangiectasia; hereditary hemorrhagic; vascular endothelial growth factor A
资金
- Leducq Foundation
- US National Institutes of Health [P30 EY026878, R01EY025979, R01 HL135582]
- European Research Council [679368]
- Fundacao para a Ciencia e a Tecnologia [CEECIND/02589/2018]
- Fundação para a Ciência e a Tecnologia [PRAXIS XXI/BD/16116/98, CEECIND/02589/2018/CP1543/CT0005] Funding Source: FCT
- European Research Council (ERC) [679368] Funding Source: European Research Council (ERC)
This study demonstrates the critical role of ALK1 in controlling endothelial cell polarization against blood flow direction and promoting vein-to-artery migration, while identifying integrin-YAP/TAZ signaling blockers as potential targets for preventing vascular malformations in patients with hereditary hemorrhagic telangiectasia.
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 ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. 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 Alk1-deficient mice. 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.
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