Endothelial Plasticity: Shifting Phenotypes through Force Feedback

Abstract

The endothelial lining of the vasculature is exposed to a large variety of biochemical and hemodynamic stimuli with different gradients throughout the vascular network. Adequate adaptation requires endothelial cells to be highly plastic, which is reflected by the remarkable heterogeneity of endothelial cells in tissues and organs. Hemodynamic forces such as fluid shear stress and cyclic strain are strong modulators of the endothelial phenotype and function. Although endothelial plasticity is essential during development and adult physiology, proatherogenic stimuli can induce adverse plasticity which contributes to disease. Endothelial-to-mesenchymal transition (EndMT), the hallmark of endothelial plasticity, was long thought to be restricted to embryonic development but has emerged as a pathologic process in a plethora of diseases. In this perspective we argue how shear stress and cyclic strain can modulate EndMT and discuss how this is reflected in atherosclerosis and pulmonary arterial hypertension.

Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

“…Canonical TGFβ/bone morphogenetic protein (BMP) signalling can activate two opposing signalling cascades, maintaining homoeostasis via phosphorylation of transcription factors SMAD1/5/8, while instigating pro-fibrotic signalling via phosphorylation of SMAD2/3 15 (Supplementary Fig. 1).…”

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

“…EndMT is the process of cellular transdifferentiation in which endothelial cells lose their endothelial-specific markers and gain a mesenchymal phenotype. 36,37 EndMT is important during embryonic vascular development and also plays a role during vascular repair. 38 However, EndMT has also been linked to various pathological conditions, including malignant 39 and fibrotic diseases.…”

Endothelial Cell Mechanotransduction in the Dynamic Vascular Environment

“…[118] Kruppel-like factors KLF2 and KLF4 are involved in suppressing EndMT by inhibition of NFκB, reduced Smad2 and TGF-β signaling, and diminished ROS formation. [119] Low levels of 0.5 Pa shear applied to non-ciliated mutant mouse embryonic ECs induced EndMT in a TGF-β /ALK5-dependent manner, as indicated by loss of CD31 and upregulation of Snail, α−SMA, and N-cadherin. Shear-induced TGF-β signaling led to a loss of KLF4, but KLF4 overexpression, cilia rescue, or TGF-β receptor disruption could prevent shear-induced EndMT.…”