Inflammatory Mechanisms Contributing to Endothelial Dysfunction

Abstract

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.

Keywords: NLRP3 inflammasome; Nf-κB; adhesion molecules; endothelial dysfunction; inflammation; selectins; shear stress.

Figure 1

Inflammatory activation of endothelial cells (ECs). (A) Stimulation of EC receptors by damage-associated molecular patterns (High mobility group box 1 (HMGB1)), inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukins (ILs)), oxidized low-density lipoproteins (oxLDL), advanced glycation end products (AGEs), and angiotensin (Ang)-II promotes nuclear factor-κB (NF-κB) signaling which results in (B) upregulation of adhesion molecules (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, E-Selectin (E-S), P-Selectin (P-S)) with subsequent monocyte (MC) adhesion and subendothelial transmigration with the aid of monocyte chemoattractant protein (MCP)-1 and its receptor C-C chemokine receptor type 2 (CCR2). Monocytes proceed to differentiate into macrophages that phagocytose oxLDL to become foam cells. (C) Injured endothelial cells release inflammatory mediators and tissue factor (TF) further promoting inflammation and coagulation, while the release of von-Willebrand factor (vWF) from the Weibel-Palade bodies results in platelet adhesion and aggregation following the binding with platelet glycoprotein (GP)1b. NLRP3: NLR family pyrin domain containing 3, TLR: toll-like receptor, RAGE: receptor of advanced glycation end products, VSMC: vascular smooth muscle cell.

Figure 2

Different properties of laminar and oscillatory shear stress under normal and pathologic conditions with implications for inflammation and endothelial dysfunction. Nrf2: nuclear factor erythroid 2–related factor 2, KLF2: Krüppel-like factor-2, Ang2: angiopoietin-2, TIE1: tyrosine kinase with immunoglobulin-like and EGF-like domains-1, YAP: yes-associated protein, TWIST1: twist-related protein-1.