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bioRxiv · 10.1101/2021.05.06.442985

Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia

Park, H.·Furtado, J.·Poulet, M.·Chung, M.·Yun, S.·Lee, S.·Sessa, W. C.·Franco, C. A.·Schwartz, M. A.·Eichmann, A.
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Abstract

BackgroundActivin receptor-like kinase 1 (ACVRL1, hereafter 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 (HHT), a devastating disorder that leads to arteriovenous malformations (AVMs). 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. MethodsUsing Cre lines that recombine in different subsets of arterial, capillary-venous or endothelial tip cells, we showed that capillary-venous Alk1 deletion was sufficient to induce AVM formation in the postnatal retina. ResultsALK1 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 VEGFR2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacological inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1 deficient mice. ConclusionsOur study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of AVM formation in HHT disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in HHT patients.

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Park, H., Furtado, J., Poulet, M., Chung, M., Yun, S., Lee, S., Sessa, W. C., Franco, C. A., Schwartz, M. A., Eichmann, A.. 2021-05-06. Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia. https://doi.org/10.1101/2021.05.06.442985

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