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

Abstract

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.

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

“…The latter two are reportedly involved in Hippo signaling (Jiang et al , 2020; Lu et al , 2021). Map3k3 is additionally involved in stress-activated protein kinase signaling and regulation of NFkB activation (Ellinger-Ziegelbauer et al , 1997; Yang et al , 2001), and recent studies show interaction with TGFβ signaling in arterial remodelling (Deng et al , 2021a; Deng et al , 2021b). Eight of the other thirteen genes encode components of G protein coupled receptor (GPCR) signaling pathways related to Cdc42 rho kinase that influences cytoskeletal regulation, cell adhesion and migration (Sakabe et al , 2017; Yoshida et al , 2021).…”

Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling

“…Furthermore, caveolin-1, itself a PAH risk factor that is regulated by shear stress forces, is required for proper membrane localization of BMPRII ( 102 , 103 ). In elegant contrast with the quiescence-promoting role for the BMPRII pathway, disturbed flow patterns stimulate arterial remodeling through a mechanism dependent upon endothelial SMAD2/3 and ALK5 signaling ( 104 , 105 ). These studies suggest an interesting model for the onset of PAH pathogenesis in which loss of BMPRII or one of its signaling partners removes a flow-regulated brake upon SMAD2/3-driven remodeling processes by pulmonary vascular ECs.…”

MicroRNAs in Mechanical Homeostasis

“…By contrast, NF-κB, which induces inflammatory genes in endothelial cells, exhibits a maximum at both low and high shear stress values with a minimum at physiological shear stress, as befits a process that is central to remodeling (Baeyens et al 2015). Smad2/3 signaling is activated with a sharp peak at low shear stress values and promotes artery inward remodeling, consistent with mechanical homeostasis (Deng et al 2021). Mechanical homeostasis via microRNAs.…”

“…The initial intrusion of plaques into artery lumens is compensated by outward (so-called Glagov) remodeling that maintains lumen diameter; however, this mechanism fails in severe disease for reasons that are not well understood (Korshunov et al 2007). However, the recent identification of Smad2/3 as key mediators of inward remodeling provides a likely answer (Deng et al 2021). Smad2/3 in endothelial cells is activated downstream of inflammatory cytokines or inflammatory disturbed flow; by contrast, in healthy arteries, Smad2/3 is suppressed by Let-7 family miRNAs (Chen et al 2012(Chen et al , 2015a.…”