Endothelial cell SMAD6 balances Alk1 function to regulate adherens junctions and hepatic vascular development. Development 2023 Nov 01;150(21)
Date
10/03/2023Pubmed ID
37787089Pubmed Central ID
PMC10629679DOI
10.1242/dev.201811Scopus ID
2-s2.0-85176385207 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
BMP signaling is crucial to blood vessel formation and function, but how pathway components regulate vascular development is not well-understood. Here, we find that inhibitory SMAD6 functions in endothelial cells to negatively regulate ALK1-mediated responses, and it is required to prevent vessel dysmorphogenesis and hemorrhage in the embryonic liver vasculature. Reduced Alk1 gene dosage rescued embryonic hepatic hemorrhage and microvascular capillarization induced by Smad6 deletion in endothelial cells in vivo. At the cellular level, co-depletion of Smad6 and Alk1 rescued the destabilized junctions and impaired barrier function of endothelial cells depleted for SMAD6 alone. Mechanistically, blockade of actomyosin contractility or increased PI3K signaling rescued endothelial junction defects induced by SMAD6 loss. Thus, SMAD6 normally modulates ALK1 function in endothelial cells to regulate PI3K signaling and contractility, and SMAD6 loss increases signaling through ALK1 that disrupts endothelial cell junctions. ALK1 loss-of-function also disrupts vascular development and function, indicating that balanced ALK1 signaling is crucial for proper vascular development and identifying ALK1 as a 'Goldilocks' pathway in vascular biology that requires a certain signaling amplitude, regulated by SMAD6, to function properly.
Author List
Kulikauskas MR, Oatley M, Yu T, Liu Z, Matsumura L, Kidder E, Ruter D, Bautch VLAuthor
Ziqing Liu PhD Assistant Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adherens JunctionsEndothelial Cells
Hemorrhage
Humans
Liver
Phosphatidylinositol 3-Kinases
Smad6 Protein
