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Review
. 2022 Jun;24(6):483-492.
doi: 10.1007/s11883-022-01023-9. Epub 2022 Apr 11.

More than Just a Monolayer: the Multifaceted Role of Endothelial Cells in the Pathophysiology of Atherosclerosis

Marion Mussbacher  1 , Klaudia Schossleitner  2 , Julia B Kral-Pointner  3   4 , Manuel Salzmann  3   4 , Astrid Schrammel  5 , Johannes A Schmid  6
Affiliations
Review

More than Just a Monolayer: the Multifaceted Role of Endothelial Cells in the Pathophysiology of Atherosclerosis

Marion Mussbacher et al. Curr Atheroscler Rep. 2022 Jun.

Abstract

Purpose of the review: In this review, we summarize current insights into the versatile roles of endothelial cells in atherogenesis.

Recent findings: The vascular endothelium represents the first barrier that prevents the entry of lipoproteins and leukocytes into the vessel wall, thereby controlling two key events in the pathogenesis of atherosclerosis. Disturbance of endothelial homeostasis increases vascular permeability, inflammation, and cellular trans-differentiation, which not only promotes the build-up of atherosclerotic plaques but is also involved in life-threatening thromboembolic complications such as plaque rupture and erosion. In this review, we focus on recent findings on endothelial lipoprotein transport, inflammation, cellular transitions, and barrier function. By using cutting-edge technologies such as single-cell sequencing, epigenetics, and cell fate mapping, novel regulatory mechanisms and endothelial cell phenotypes have been discovered, which have not only challenged established concepts of endothelial activation, but have also led to a different view of the disease.

Keywords: Atherosclerosis; Endothelial cells; Endothelial dysfunction.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Multifaceted role of endothelial cells in atherogenesis. Under homeostatic conditions (upper part of the scheme), endothelial cells (EC) are covered by a dense glycocalyx and constantly release nitric oxide (NO), which is synthesized by endothelial NO synthase (eNOS). Tissue plasminogen activator (t-PA), antithrombin III (ATIII), and prostacyclin, which is produced by cyclooxygenases (COX), prevent platelet activation and blood clotting. Bone marrow-derived endothelial progenitor cells (EPC) allow EC renewal. Smooth muscle cells (SMCs) are in a “contractile” state, enabling the adjustment of the vascular tone. Under atherosclerotic conditions (lower part of the scheme), the glycocalyx is degraded by plasminogen activator inhibitor (Serpine1) and EC permeability is increased due to downregulation of junctional proteins (e.g., occludin and claudin-5). Mechanosensitive cation channels such as Piezo1 detect turbulent flow and cause the downregulation of Krüppel-like factor 2 (Klf2) and forkhead box O1 (Foxo-1). Endothelial dysfunction is characterized by reduced eNOS expression and decreased NO bioavailability due to elevated levels of reactive oxygen species (ROS). Transcytosis of low-density lipoproteins (LDLs) is mediated by scavenger receptor class B (SR-B1) and potentially activin-like kinase (ALK1). EC inflammation facilitates leukocyte recruitment by increasing the surface expression of E-selectin, vascular cellular adhesion molecule 1 (VCAM), and intercellular adhesion molecule 1 (ICAM). Activation of NF-κB is further enhanced by high mobility group box1 (HMGB1) and initiates the assembly of the EC inflammasome, resulting in the release of interleukin 1β (IL-1β). Endothelial-to-mesenchymal-transition (EndMT) is characterized by decreased expression of CD31 and eNOS/NOS3 as well as increased levels of fibroblast activation protein (FAP) and alpha-actin 2 (ACTA). Whereas transforming growth factor β (TGFβ) promotes EndMT and SMC transition towards a macrophage-like state, fibroblast-like growth factor (FGF) inhibits EndMT. The (athero)thrombotic risk is increased by endothelial expression of tissue factor (TF) and release of von Willebrand factor (vWF). Endothelial apoptosis increases the number of circulating CD146 + ECs in the blood stream
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