RT Journal Article
SR Electronic
T1 SMAD6 Integrates Endothelial Cell Homeostatic Flow Responses Downstream of Notch
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.02.184820
DO 10.1101/2020.07.02.184820
A1 Dana L Ruter
A1 Ziqing Liu
A1 Kimlynn M Ngo
A1 X Shaka
A1 Allison Marvin
A1 Danielle B Buglak
A1 Elise J Kidder
A1 Victoria L Bautch
YR 2020
UL http://biorxiv.org/content/early/2020/07/03/2020.07.02.184820.abstract
AB Laminar shear stress regulates blood vessel morphogenesis and subsequent quiescence, leading to vascular homeostasis. Although important for vessel function, how vascular homeostasis is set up and maintained is poorly understood. SMAD6, a scaffold for several signaling pathways, is expressed in developing arteries and its expression is flow-regulated. We found that SMAD6 is essential for endothelial cell flow-mediated responses downstream of the mechanosensor Notch1. Endothelial cells with reduced SMAD6 levels failed to align under homeostatic laminar shear flow, while forced SMAD6 expression rescued misalignment induced by reduced Notch1 signaling. SMAD6-dependent homeostatic laminar flow responses required the Notch ligand Dll4 and Notch transcriptional activity. Mechanistically, neither the N-terminal nor the C-terminal domain of SMAD6 alone rescued flow alignment upon loss of Notch signaling. Endothelial cells with reduced Smad6 levels had compromised barrier function, and RNA profiling revealed upregulation of proliferation-associated genes and down regulation of junction-associated genes. Among junction-related genes affected by SMAD6 levels, the proto-cadherin PCDH12 was upregulated by homeostatic flow and required for proper flow-mediated endothelial cell alignment. Thus, SMAD6 is a critical integrator of flow-mediated signaling inputs downstream of Notch1, as vessels transition from an angiogenic to a homeostatic phenotype.Competing Interest StatementThe authors have declared no competing interest.