Endothelial Cell Phenotype, a Major Determinant of Venous Thrombo-Inflammation

Abstract

Reduced blood flow velocity in the vein triggers inflammation and is associated with the release into the extracellular space of alarmins or damage-associated molecular patterns (DAMPs). These molecules include extracellular nucleic acids, extracellular purinergic nucleotides (ATP, ADP), cytokines and extracellular HMGB1. They are recognized as a danger signal by immune cells, platelets and endothelial cells. Hence, endothelial cells are capable of sensing environmental cues through a wide variety of receptors expressed at the plasma membrane. The endothelium is then responding by expressing pro-coagulant proteins, including tissue factor, and inflammatory molecules such as cytokines and chemokines involved in the recruitment and activation of platelets and leukocytes. This ultimately leads to thrombosis, which is an active pro-inflammatory process, tightly regulated, that needs to be properly resolved to avoid further vascular damages. These mechanisms are often dysregulated, which promote fibrinolysis defects, activation of the immune system and irreversible vascular damages further contributing to thrombotic and inflammatory processes. The concept of thrombo-inflammation is now widely used to describe the complex interactions between the coagulation and inflammation in various cardiovascular diseases. In endothelial cells, activating signals converge to multiple intracellular pathways leading to phenotypical changes turning them into inflammatory-like cells. Accumulating evidence suggest that endothelial to mesenchymal transition (EndMT) may be a major mechanism of endothelial dysfunction induced during inflammation and thrombosis. EndMT is a biological process where endothelial cells lose their endothelial characteristics and acquire mesenchymal markers and functions. Endothelial dysfunction might play a central role in orchestrating and amplifying thrombo-inflammation thought induction of EndMT processes. Mechanisms regulating endothelial dysfunction have been only partially uncovered in the context of thrombotic diseases. In the present review, we focus on the importance of the endothelial phenotype and discuss how endothelial plasticity may regulate the interplay between thrombosis and inflammation. We discuss how the endothelial cells are sensing and responding to environmental cues and contribute to thrombo-inflammation with a particular focus on venous thromboembolism (VTE). A better understanding of the precise mechanisms involved and the specific role of endothelial cells is needed to characterize VTE incidence and address the risk of recurrent VTE and its sequelae.

How to optimize the prevention of post-thrombotic syndrome: recent advances

“…Endothelial cells are essential regulators of thrombus resolution [52]. They regulate extravasation and activation of leukocytes, regulate fibrinolysis, endothelialize the damaged vein and thrombus, form neovascular channels and modulate fibrosis [5].…”

“…They regulate extravasation and activation of leukocytes, regulate fibrinolysis, endothelialize the damaged vein and thrombus, form neovascular channels and modulate fibrosis [5]. While these cells accelerate thrombus resolution, their dysfunction and reduced survival can have detrimental effects on the thrombus resolution and vein wall fibrosis [52,53]. Thus, endothelium-protective therapy in patients with DVT might be beneficial.…”

Link between sterile inflammation and cardiovascular diseases: Focus on cGAS-STING pathway in the pathogenesis and therapeutic prospect

“…Mechanically, different from canonical cGAS signaling, mitochondria-induced endothelial STING activation which was mediated by IFN-inducible factor 16 (IFI16) triggered the increases of NF-κB-mediated adhesion molecules ( 65 ). Besides, as an important driver of vascular inflammation, endothelial cells play an important role in the onset of vascular injury or chronic metabolic disease-associated tissue inflammatory injury ( 66 ). Obesity is a metabolic disorder that fosters the occurrence and complication of diverse disease, which goes along with inflammation ( 67 , 68 ).…”

Endothelial cell–mediated venous thrombosis

“…However, the endothelial phenotype may convert to a prothrombotic state with various systemic or local insults and is likely central to thrombotic events. 4 Experimentally, venous stasis causes endothelial gaps and denudation, with rapid TF expression. 5 The strengths of this report are several; first, the well-controlled and elegantly performed in vitro experiments with small interfering RNA and direct pathway inhibitors convincingly demonstrate how Gab2 and downstream processes promote an endothelial prothrombotic state.…”

“…Alternatively, altering the endothelial phenotype may also inhibit fibrosis. 4 Taken together, the Gab2 pathway is an intriguing endothelial cell target, with potential human translation. Confirmation of these results by other investigators would be appropriate, and examination of the later effects of mepazine as an MALT1 inhibitor on the later cellular and VT resolution functions is a logical next step; definition of any off-target effects is essential as well.…”