Extracellular substrate stiffness-mediated regulation of endothelial cell function

Abstract

Endothelial cells sense extracellular substrate stiffness and adapt their function. Vascular or arterial stiffening observed during hypertension, arteriosclerosis, and acute inflammation may be involved in endothelial cell dysfunction; however, the impact of substrate stiffness on endothelial cell functions remains elusive. First, we confirmed that endothelial cells cultured on softer substrates not only elongate cellular aspects but also attenuate yes-associated protein 1 (YAP) activation compared to cells on stiffer substrates. Endothelial cells on softer substrates upregulated the vascular endothelial growth factor receptors mRNA expression. Next, we found that endothelial cells on softer substrates induced delta-like ligand 4 (Dll4) expression via YAP1 deactivation and Notch1 activation. Moreover, endothelial cells on soft substrates induced suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression, all of that partially regulated by the YAP-Dll4-Notch pathway. Our results indicated that endothelial cells modulate cell functions in response to substrate stiffness through activating the YAP-Dll4-Notch pathway. These suggested that vascular or arterial stiffening promotes endothelial cell dysfunction leading to be the onset of vascular inflammatory diseases.