Endothelial-Mesenchymal Transition in Cardiovascular Disease

Abstract

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane, and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, that is, a phenotypic modulation, that is sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating endothelial-to-mesenchymal transition have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increase permeability, which facilitates leukocyte trafficking, whereas endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete endothelial-to-mesenchymal transition proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In proadaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in maladaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how TGF (transforming growth factor) β influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases.

Keywords: cardiovascular disease; endothelial cells; mitral valve insufficiency; phenotype; transforming growth factor.

Figure 1.

Endothelial cells exposed to TGFβ and cytokines begin EndMT by loosening junctions between endothelial cells (1), which facilitates migration into the perivascular compartment (2). The mesenchymal transition (3) can be partial, wherein cells exhibit both endothelial and mesenchymal characteristics. This state can be transient – recently referred to as endothelial to mesenchymal activation- as the cells revert to a functional endothelial phenotype. Fully transitioned cells with diminished endothelial and increased mesenchymal functions can contribute to tissue repair but in disease settings often exacerbate fibrosis.

Figure 2.

Mitral VECs in culture undergoing EndMT. Cells were co-stained with anti-VE-cadherin (green), anti-α-SMA (red) and DAPI (blue) to highlight nuclei. A 72-hour stimulus converted many VE-cadherin-positive VECs within the cobblestone monolayer to α-SMA-positive/VE-cadherin-positive cells (yellow/orange) with mesenchymal morphology, indicating partial EndMT. Scale bar, 50μm.