Scientia 2020

Page 44

Endothelial Cell Diversity & Heterogeneity Arvind Muruganantham¹ ¹Department of Biology, Baylor University, Waco, TX

Review Article

Abstract Given the extensive functional, phenotypic, and genotypic diversity of the endothelium, endothelial cell biology remains a poorly investigated area of research in relation to its relative importance to human health. As the lining of the body’s vasculature, the endothelium heavily mediates the coagulation cascade by controlling the activation of platelets through vWF presentation and formation of the fibrin-platelet matrix through TF secretion. Apart from maintaining proper hemostasis, the endothelium is also largely responsible for mediating immune response via leukocyte trafficking. Endothelium response to local cytokine signaling prompts leukocyte extravasation through chemoattraction (via cytokines), rolling adhesion (via CAMs), tight adhesion (via integrins), and transmigration (via PECAM). Furthermore, tumor angiogenesis, a process highly investigated due to its importance to tumor cell proliferation and metastasis,is also endothelium-mediated. By hijacking proangiogenic pathways, such as VEGF and cytokine signaling, cancer cells promote sprouting angiogenesis to the site of the tumor to obtain a steady supply of nutrients and growth factors. In order to carry out the endothelium’s wide-ranging functions, vascular endothelial cell phenotypes are influenced by a cocktail of developmental influences arising as early as amniotic development and environmental cues from the surrounding tissue. Adding another layer of heterogeneity, recent studies have shown phenotypically equivalent endothelial cells engaging in noise-mediated stochastic phenotype switching to create mosaic heterogeneity in endothelial cells arising from the same vascular bed. Further understanding the diverse and complex functions of endothelial cells, at both the cellular and population level, will provide insight into drug development for a myriad of diseases.

Introduction The endothelium, the single layer of cells that lines the cavities of the body and its vasculature, is involved in many critical biological processes and disease pathologies. Endothelial cells are products of mesoderm-derived hemangioblasts that form cell clusters, known as blood islands, during amniotic development. The outer cells of the blood islands further flatten to differentiate into vascular endothelia while the core of the blood cells become hematopoietic cells (Dyer & Patterson, 2010). As the vascular endothelium progresses in the developmental process, it gains exposure to signals that results in the cell type’s widespread diversity and heterogeneity via environmental cues. Through a combination of paracrine signaling and cellular sensors, cells modulate their gene expression patterns to match that of their respective environments (Zhang & Friedman, 2013). Given the endothelium’s multifaceted roles throughout the body, the ability of endothelial cells to become highly specialized for their environment is crucial to maintaining proper vascular physiology.

Endothelium Mediated Coagulation Serving as the lining of the body’s vasculature, naturally, the endothelium is heavily involved in many of the hemostatic

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pathways triggered by vascular injury. Typically, coagulation is thought to occur in three distinct phases (Versteeg, Heemskerk, Levi, & Reitsma, 2013). First, sub-endothelial collagen is exposed at the site of injury and mediates the initial round of platelet adhesion to the collagen surface via von Willebrand factor (vWF). Activated endothelial cells then secrete tissue factor (TF) to combine with activated circulating coagulation factor VII (fVIIa) to form the TF/fVIIa complex, which in turn increases thrombin levels to form activated platelet aggregates. Finally, thrombin proteolytically cleaves various coagulation factors and fibronectin to interlock fibrin chains into a cohesive fibrin matrix, thus creating an effective barricade to protect against infection and rapid blood loss (Figure 1). Endothelial cells serve as master regulators of the coagulation cascade through a two-fold mechanism: presentation of vWF on the luminal surface of vasculature to prompt activated platelet adhesion to the collagen surface and TF secretion to create a cross-linked fibrin matrix upon which activated platelets can form aggregates (Yau, Teoh, & Verma, 2015). After the injury has been healed, endothelial cells also contribute to the breakdown of the dense platelet-fibrin matrix through the release of fibrinolytic enzyme activators, such as tissue plasminogen activator (t-PA)(Rajendran et al., 2013). In unison with other serine proteases, t-PA catalyzes the


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