Endothelial Barrier and Its Abnormalities in Cardiovascular Disease

Abstract

Endothelial cells (ECs) form a unique barrier between the vascular lumen and the vascular wall. In addition, the endothelium is highly metabolically active. In cardiovascular disease such as atherosclerosis and hypertension, normal endothelial function could be severely disturbed leading to endothelial dysfunction that then could progress to complete and irreversible loss of EC functionality and contribute to entire vascular dysfunction. Proatherogenic stimuli such as diabetes, dyslipidemia, and oxidative stress could initiate endothelial dysfunction and in turn vascular dysfunction and lead to the development of atherosclerotic arterial disease, a background for multiple cardiovascular disorders including coronary artery disease, acute coronary syndrome, stroke, and thrombosis. Intercellular junctions between ECs mediate the barrier function. Proinflammatory stimuli destabilize the junctions causing the disruption of the endothelial barrier and increased junctional permeability. This facilitates transendothelial migration of immune cells to the arterial intima and induction of vascular inflammation. Proatherogenic stimuli attack endothelial microtubule function that is regulated by acetylation of tubulin, an essential microtubular constituent. Chemical modification of tubulin caused by cardiometabolic risk factors and oxidative stress leads to reorganization of endothelial microtubules. These changes destabilize vascular integrity and increase permeability, which finally results in increasing cardiovascular risk.

Keywords: cardiovascular disease; cell-to-cell junctions; endothelial barrier; endothelial intercellular junctions; endothelium.

Figure 1

The formation of vesicles (50–90 nm in diameter) and caveolae along the luminal surface of endothelial cells (A–C). In the cytoplasm, vesicles often aggregate and fuse, forming vesicular structures of larger sizes (A,B). Some plasmalemmal vesicles can fuse with cell membrane in the area of EC intercellular contacts (C). Transmission electron microscopy (TEM). Scale bars = 100 nm (A–C). Images are adapted from Bobryshev (1983).

Figure 2

Endothelial function in the norm. Arterial endothelial cells are involved in the maintenance of vascular homeostasis by providing balanced release of vasodilatating/vascoconscticting factors and prothrombotic/antithrombotic substances that inhibits the endothelial adhesion of leukocytes and thus, prevents the initiation of vascular inflammation.

Figure 3

Penetration of a blood cell through the endothelium into the arterial intima. Scanning electron microscopy (SEM). Scale bar = 5 μm. Image is adapted from Bobryshev (1983).

Figure 4

Scheme of a protein structure of endothelial intercellular junctions (EIJs). EIJs consist of tight junctions (TJ) and adherens junctions (AJ) and join two adjacent endothelial cells (Hirase and Node, ; Dejana and Orsenigo, 2013). In TJ, membrane proteins are represented by occludin, claudins, and junctional adhesion molecules (JAM). Tight junction proteins (TJP1, TJP2, and TJP3) are cytosolic TJ proteins involved in linking TJ membrane proteins to the cytoskeletal actin. Cingulin is another cytoplasmic TJ protein, which is able to interact with TJPs, occludin, and actin and therefore to link membrane TJ proteins with the cytoskeleton. In AJ, a membrane protein component is represented by vascular-endothelial (VE)-cadherin. p120, β-catenin, and plakoglobin/γ-catenin bind to the C-terminal domain of VE-cadherin. β-catenin interacts with α-catenin that with help of plakoglobin/γ-catenin contributes to the signal transduction from VE-cadherin to the cytoskeleton. α-actinins and vinculain are microfilamentous components that mediate VE-cadherin-dependent mechanotransduction to the cytoskeleton.