Journal Article

Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling

Huang, Billy, Min, Elizabeth, Baeyens, Nicolas, Su, Bing, Hu, Rui, Acheampong, Angela, Deng, Hanqiang, Zhuang, Zhen W., Eichmann, Anne, Chen, Minghao, Simons, Michael, McEntee, Kathleen, Zarkada, Georgia, Schwartz, Martin A., Afolabi, Titilayo, Coon, Brian G., Liu, Fang

2021

Overview

Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-β family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-β signaling.

• Publisher: National Academy of Sciences
• Subject: Animals / Arteriosclerosis / Atherosclerosis / Biological Sciences / Blood flow / Blood vessels / Bone morphogenetic proteins / Carotid Arteries - cytology / Carotid Arteries - physiology / Carotid Artery Diseases - metabolism / Carotid Artery Diseases - pathology / Carotid Artery Diseases - prevention & control / Cell Biology / Cyclin-dependent kinase / Cyclin-dependent kinases / Endothelial cells / Endothelial Cells - cytology / Endothelial Cells - physiology / Fluid flow / Gene expression / Growth factors / Humans / Kinases / Krueppel-like factor / Localization / Male / Mechanical stimuli / Mice / Mice, Inbred C57BL / Neuropilin / Nuclear transport / Phosphorylation / Proteins / Regulatory mechanisms (biology) / Shear stress / Signal Transduction / Signaling / Smad protein / Smad2 protein / Smad2 Protein - genetics / Smad2 Protein - metabolism / Smad3 Protein - genetics / Smad3 Protein - metabolism / Stress, Mechanical / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism / Translocation / Vascular Remodeling / Veins & arteries