Shear stress modulates TGF‐beta signaling and EMT in endothelial cells

Abstract

Blood flow and concomitant shear stress play an instrumental role in the development of the cardiovascular system as endothelial cells (EC) functionally respond to shear. During cardiac development areas of high shear stress, i.e. the outflow and atrioventricular cushions, are characterized by high expression of Krüppel‐like factor 2 (Klf2) and by epithelial to mesenchymal transformation (EMT). In the adult situation exposure of EC to high and pulsatile flow induces a quiescent phenotype associated with high levels of Klf2 and a lack of EMT. Low and disturbed flow renders EC pro‐proliferative, marked by the activation of transforming growth factor‐beta (TGF‐β) signaling. Interestingly, embryonic EMT in areas of high shear is also associated with the activation of the TGF‐β pathway. In this study we investigated the shear stress modulation of TGF‐β signaling in EC. Cultured mouse embryonic EC were subjected to various flow profiles and levels in a shear stress bioreactor. The induced response was assessed by analysis of Klf2, TGF‐β ligands, TGF‐β serine/threonine kinase receptors Alk1 and Alk5, their pathway components, inhibitory Smads and downstream signaling targets. In order to discriminate between Alk1 and Alk5 signaling, Alk5 activity was selectively inhibited. The results indicate an intricate relation between flow induced signaling and the activation of TGF‐beta pathway and EMT in endothelial cells