Translocating transcription factors in fluid shear stress-mediated vascular remodeling and disease

Abstract

Endothelial cells are exposed to fluid shear stress profiles that vary in magnitude, pulsatility, and directionality due to regional variations in blood vessel structure. Laminar flow at physiological levels is atheroprotective; multidirectional or reversing low (disturbed) flow promotes inflammation and disease; and high or low laminar flow promote outward or inward remodeling, respectively. However, our understanding of how endothelial cells discern these different flow profiles and regulate gene expression accordingly is limited. This article reviews recent studies that identify the TGFβ/Smad, Notch, Yap/Taz, and Wnt/β-catenin pathways as important mediators of flow profile- and magnitude-dependent signaling.

Figure 1:. Summary of pathways

Physiological laminar shear stress activates Alk1/Endoglin (with an unidentified type II receptor denoted RII) to induce Smad1/5/8 phosphorylation and entry into the nucleus to induce expression of target genes that promote vascular stabilization. Laminar shear, possibly acting through integrins, also induces Yap/Taz phosphorylation and cytoplasmic retention/degradation to inhibit signaling. Notch1, in concert with DLL ligands, is stimulated by flow to induce release of the intracellular domain (ICD), which translocates to the nucleus to induce Cx37, which signals to induce expression of the p27 cell cycle inhibitor. By contrast, disturbed shear stress, acting through yet-to-be identified type I, II and III receptors, promotes Smad2/3 phosphorylation. DSS also triggers Yap/Taz dephosphorylation and activation, and inhibits β-Catenin degradation, to drive its nuclear localization, pairing with TCFs and target gene expression.