PT  - JOURNAL ARTICLE
AU  - Elizabeth Min
AU  - Nicolas Baeyens
AU  - Rui Hu
AU  - Zhenwu Zhuang
AU  - Minghao Chen
AU  - Billy Huang
AU  - Georgia Zarkada
AU  - Angela Acheampong
AU  - Kathleen McEntee
AU  - Michael Simons
AU  - Anne Eichmann
AU  - Martin A. Schwartz
TI  - Activation of Smad 2/3 signaling by low shear stress mediates artery inward remodeling
AID  - 10.1101/691980
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 691980
4099  - http://biorxiv.org/content/early/2019/07/05/691980.short
4100  - http://biorxiv.org/content/early/2019/07/05/691980.full
AB  - Rationale Blood vessel remodeling in response to changes in tissue demand is an important aspect of fitness and is often compromised in vascular disease. Endothelial cell (EC) sensing of fluid shear stress (FSS) governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels.Objective The purpose of this study was to understand how shear stress-regulated Smad 2/3 contributes to artery remodeling.Methods and Results We found that shear stress induces Smad 2/3 phosphorylation, nuclear translocation, and gene expression in ECs. Nuclear translocation and gene expression are maximal at low and decrease at high FSS. Reducing flow in the mouse carotid by ligation of branch vessels induces Smad2 nuclear localization in vivo. Activation of Smad 2/3 by FSS requires the Type I TGFβ family receptor Alk5 and the transmembrane protein Neuropilin-1. Flow activation of Smad 2/3 is mediated by increased sensitivity to BMP9 but not BMP10 or TGFβ. By contrast, flow activation of Smad 1/5 is maximal at physiological FSS and requires BMP9 or 10 binding to Alk1 and Endoglin. EC-specific deletion of Alk5 in mice blocks low flow-induced inward remodeling after carotid ligation.Conclusions Together, these data elucidate a novel pathway that mediates low flow-induced inward artery remodeling. These results may be relevant to inward remodeling in diseased vessels where Smad 2/3 is activated by pathological stimuli.