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Transcriptome analysis of the role of SMAD6 in mediating endothelial cell response to laminar shear stress by high throughput RNA sequencing

ABSTRACT: Laminar shear stress regulates blood vessel morphogenesis and subsequent quiescence, but how endothelial cells (EC) enact and maintain the vascular homeostasis required in most vessels for proper vessel function 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, and that it functions downstream of the mechanosensor Notch1. Endothelial cells with reduced SMAD6 levels failed to align under stable laminar shear flow that promotes vascular homeostasis, while forced SMAD6 expression rescued misalignment induced by reduced Notch1 signaling. SMAD6-dependent homeostatic laminar flow 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 has 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147036 | GEO | 2021/03/29

REPOSITORIES: GEO

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Project description:Giantsos-Adams2013 - Growth of glycocalyx under static conditions This model is described in the article: Heparan Sulfate Regrowth Profiles Under Laminar Shear Flow Following Enzymatic Degradation. Giantsos-Adams KM, Koo AJ, Song S, Sakai J, Sankaran J, Shin JH, Garcia-Cardena G, Dewey CF. Cell Mol Bioeng 2013 Jun; 6(2): 160-174 Abstract: The local hemodynamic shear stress waveforms present in an artery dictate the endothelial cell phenotype. The observed decrease of the apical glycocalyx layer on the endothelium in atheroprone regions of the circulation suggests that the glycocalyx may have a central role in determining atherosclerotic plaque formation. However, the kinetics for the cells' ability to adapt its glycocalyx to the environment have not been quantitatively resolved. Here we report that the heparan sulfate component of the glycocalyx of HUVECs increases by 1.4-fold following the onset of high shear stress, compared to static cultured cells, with a time constant of 19 h. Cell morphology experiments show that 12 h are required for the cells to elongate, but only after 36 h have the cells reached maximal alignment to the flow vector. Our findings demonstrate that following enzymatic degradation, heparan sulfate is restored to the cell surface within 12 h under flow whereas the time required is 20 h under static conditions. We also propose a model describing the contribution of endocytosis and exocytosis to apical heparan sulfate expression. The change in HS regrowth kinetics from static to high-shear EC phenotype implies a differential in the rate of endocytic and exocytic membrane turnover. This model is hosted on BioModels Database and identified by: MODEL1609100001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Transcriptome analysis of the role of SMAD6 in mediating endothelial cell response to laminar shear stress by high throughput RNA sequencing

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