A Computational Model of the Endothelial to Mesenchymal Transition.

Nathan Weinstein,Elena R Álvarez-Buylla,Luis Mendoza

doi:10.3389/fgene.2020.00040

Nathan Weinstein, Elena R Álvarez-Buylla + Show 1 more

Open Access

https://doi.org/10.3389/fgene.2020.00040

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Abstract

Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

Highlights

The circulatory system allows the body to efficiently transport oxygen and nutrients to all the constituent cells of animals through an intrincate network of blood vessels
These changes lead to the activation of the transcription factors SNAI1, SNAI2, TWIST1, ZEB1, and SPI1(ZEB2), resulting in the repression of the expression of endothelial markers, VEGFR2, PECAM1, VECadherin, TIE1, TIE2, and vWF accompanied by the augmented expression of mesenchymal markers including asmooth muscle actin (aSMA), N-cadherin, and Collagen I//II
endothelial-to-mesenchymal transition (EndMT) is defined by the loss of endothelial cells (ECs) adhesion, the conversion of endothelial apical-basal polarity to front end-back end polarity, and a marked decrease in EC markers accompanied by increased mesenchymal cells (MCs) marker expression

Summary

Introduction

The circulatory system allows the body to efficiently transport oxygen and nutrients to all the constituent cells of animals through an intrincate network of blood vessels. Capillaries are the smallest blood vessels, communicating arterioles and venules; they are composed of a single layer of endothelial cells (ECs), and are partially covered by mural cells called pericytes (PCs). EndMT is triggered either by changes in the concentration of WNT, NOTCH, FGF, or TGF ligands in the extracellular microenvironment, reduced oxygen availability or shear stress. These changes lead to the activation of the transcription factors SNAI1, SNAI2, TWIST1, ZEB1, and SPI1(ZEB2), resulting in the repression of the expression of endothelial markers, VEGFR2, PECAM1, VECadherin, TIE1, TIE2, and vWF accompanied by the augmented expression of mesenchymal markers including aSMA, N-cadherin, and Collagen I//II. During EndMT, ECs lose cell-to-cell adhesion and luminobasal polarity, gaining migratory and invasive potential (Figure 1B) (Gong et al, 2017; Jackson et al, 2017)

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