Endothelium

Endothelium is of mesodermal origin. Both blood and lymphatic capillaries are composed of a single layer of endothelial cells called a monolayer. In straight sections of a blood vessel, vascular endothelial cells typically align and elongate in the direction of fluid flow.[2][3]

Endothelium lines the inner wall of vessels, shown here.

Endothelial cells are involved in many aspects of vascular biology, including:

• Barrier function - the endothelium acts as a semi-selective barrier between the vessel lumen and surrounding tissue, controlling the passage of materials and the transit of white blood cells into and out of the bloodstream. Excessive or prolonged increases in permeability of the endothelial monolayer, as in cases of chronic inflammation, may lead to tissue edema/swelling. Altered barrier function is also implicated in cancer extravasation.[6]
• Blood clotting (thrombosis & fibrinolysis). The endothelium normally provides a non-thrombogenic surface because it contains, for example, heparan sulfate which acts as a cofactor for activating antithrombin, a protease that inactivates several factors in the coagulation cascade.
• Inflammation[7]. Endothelial cells actively signal to immune cells[8] during inflammation
• Formation of new blood vessels (angiogenesis)
• Vasoconstriction and vasodilation, and hence the control of blood pressure
• Repair of damaged or diseased organs via an injection of blood vessel cells[9]
• Angiopoietin-2 works with VEGF to facilitate cell proliferation and migration of endothelial cells

Angiogenesis is a crucial process for embryonic and fetal development and organ growth[10]. The process is triggered by tissue hypoxia or insufficient oxygen tension leading to the new development of blood vessels lined with endothelial cells. Angiogenesis is a tightly regulated event that is balanced by pro- and antiangiogenic signals including integrins, chemokines, angiopoietins, oxygen sensing agents, junctional molecules and endogenous inhibitors.[11]

The general outline of the process is

• activating signals binding to surface receptors of vascular endothelial cells.
• activated endothelial cells release proteases leading to the degradation of the basement membrane
• endothelial cells are freed to migrate from the existing blood vessels and begin to proliferate to form extensions towards the source of the angiogenic stimulus.

Endothelial dysfunction, or the loss of proper endothelial function, is a hallmark for vascular diseases, and is often regarded as a key early event in the development of atherosclerosis. Impaired endothelial function, causing hypertension and thrombosis, is often seen in patients with coronary artery disease, diabetes mellitus, hypertension, hypercholesterolemia, as well as in smokers. Endothelial dysfunction has also been shown to be predictive of future adverse cardiovascular events, and is also present in inflammatory disease such as rheumatoid arthritis and systemic lupus erythematosus.

Endothelial dysfunction is a result of changes in endothelial physiology[12][13]. In response to lipid accumulation and proinflammatory stimuli, endothelial cells become activated, which is characterized by the expression of adhesion molecules such as E-selectin, VCAM-1 and ICAM-1[14]. Additionally, transcription factors including AP-1 and NF-κB  become activated, leading to up-regulated expression of proinflammatory cytokines, such as IL-1, TNFα and IFNγ[15][16]. The proatherogenic profile expressed by the endothelial cells promotes accumulation of lipids and lipoproteins in the intima, and subsequent recruitment of leukocytes and platelets, as well as proliferation of smooth muscle cells, leading to fatty streak formation. The lesions formed in the intima, and persistent inflammation lead to desquamation of endothelium, which disrupts the endothelial barrier, leading to injury and consequent dysfunction[17]. In contrast, inflammatory stimuli also activate NF-κB induced expression of the deubiquitinase A20 (TNFAIP3), which has been shown to intrinsically repair the endothelial barrier [18].

One of the main mechanisms of endothelial dysfunction is the diminishing of nitric oxide, often due to high levels of asymmetric dimethylarginine, which interfere with the normal L-arginine-stimulated nitric oxide synthesis and so leads to hypertension. The most prevailing mechanism of endothelial dysfunction is an increase in reactive oxygen species, which can impair nitric oxide production and activity via several mechanisms.[19] The signalling protein ERK5 is essential for maintaining normal endothelial cell function.[20] A further consequence of damage to the endothelium is the release of pathological quantities of von Willebrand factor, which promote platelet aggregation and adhesion to the subendothelium, and thus the formation of potentially fatal thrombi.

In cancer therapy the development and delivery of anti-angiogenic drugs is a very promising path and restoring vascular homeostasis holds great potential for the treatment of ischemic tissue diseases [21]

In August 2019, a mouse model study led by Joshua Scallan, PhD, assistant professor of molecular pharmacology and physiology at USF Health Morsani College of Medicine, identified never before seen cellular processes controlling development of the small valves inside lymphatic vessels, which prevent lymph fluid from flowing the wrong way back into tissues. According to the study, the one-way valves work with muscles to help propel lymph fluid through the body and regulate flow. These groundbreaking findings suggest that targeting the signaling pathways involved in creating and maintaining lymphatic valves may lead to a viable therapy option for patients diagnosed with lymphedema. [22]

In 1958 Todd demonstrated that endothelium in human blood vessels have fibrinolytic activity.[23][24]

• Anatomy photo: Circulatory/vessels/capillaries1/capillaries3 - Comparative Organology at University of California, Davis, "Capillaries, non-fenestrated (EM, Low)"
• Histology image: 21402ooa – Histology Learning System at Boston University
• Endothelium Journal of Endothelial Cell Research, Informa Healthcare
• Endothelium and inflammation
• Platelet Activation, University of Washington