Endothelium: The Trivial Fence Became a Powerful Gatekeeper of Vascular Health

Abstract

In this issue of Angiology, Poredos et al reviewed the clinical implications of endothelial dysfunction. They stated that the endothelium acts as both an initiating and stimulating factor for the progression of atherosclerotic cardiovascular (CV) disease; it has an independent role for the prediction of CV events. These authors concluded that the deterioration of endothelial function can be monitored and it should be a therapeutic target for the prevention and treatment of atherosclerotic disease. Initially, the endothelium was believed to just be a passive barrier. It is now considered to play a crucial role in maintaining vascular health. Indeed, the vascular endothelium is a selectively permeable barrier between the intravascular circulation and extravascular environment providing a nonthrombogenic lining. Its anatomic location allows its interaction not only with circulating blood components and cells but also with cells inside the vessel wall. The endothelium regulates the transport of macromolecules between the vascular lumen and vascular smooth muscles by several mechanisms; through the endothelial cells themselves, by diffusion within the endothelial cell membrane, through endothelial cell-to-cell junctions, through endothelial gaps, or via vesicular transport. A number of physiologic and pathophysiologic stimuli can induce, acutely and chronically, remarkable changes in endothelial permeability. Acute inflammatory mediators (eg, thrombin, histamine) can stimulate the opening of endothelial intercellular junctions. Vascular endothelial growth factors are key regulators of vascular permeability via nitric oxide synthase (NOS) regulation. Fluid shear stress, the lateral force exerted by flowing blood, also influences endothelial permeability. It is known that endothelium exposed to low wall shear stress is more likely to have elevated macromolecule permeability. Indeed, the accumulation of low density lipoprotein (LDL) and subsequently the development of atherosclerotic lesions occurs at vessel segments exposed to low, disturbed, or oscillating flow, while laminar flow and high shear stress are seemingly atheroprotective. Regarding lifestyle and atherosclerosis, exposure to cigarette smoke injures the endothelium, resulting in increased arterial permeability and increased LDL accumulation. Moreover, high fat diets may lead to endothelial tight junction disruption through lipoxygenase and its metabolite hydroxyeicosatetraenoic acid. However, high density lipoprotein (HDL) and physical exercise have been shown to maintain endothelial barrier function. Exercise maintains endothelial barrier function due to increasing blood flow and shear stress and release of “vasoprotective” molecules such as NO and prostacyclin (PGI2). Overall, a number of harmful stimuli (inflammatory mediators, environmental toxins, hemodynamic forces) can contribute to endothelial dysfunction by increasing endothelial permeability, allowing subendothelial arterial lipid accumulation and the initiation of the atherosclerotic plaque development, while others (eg, HDL and exercise) protect against atherosclerosis. Cardiovascular tone throughout the vascular tree is mainly maintained by the smooth muscle response to sympathetic/ parasympathetic nervous system stimulation. Endothelial cells play a significant role in the local regulation of vascular tone by endothelial-derived vasodilators (NO, PGI2, endothelialderived relaxing factors) as well as endothelial-derived vasoconstrictors (endothelin-1, angiotensin-II, and vasoconstrictor prostaglandins). While the endothelium has an “active anti-thrombotic” function, endothelial dysfunction leads to a disturbed hemostatic balance between thrombotic (thromboxane A2, von Willebrand factor, fibronectin and thrombospondin, factor V) and fibrinolytic (PGI2, NO, heparin-like molecules, thrombomodulin, tissue plasminogen activator, urokinase plasminogen activator inhibitor-1) factors at sites of vascular injury. MicroRNAs (miRNAs), short sequences of noncoding RNA which regulate genes at the post-transcriptional level, are actively secreted by endothelial cells under physiological and pathophysiological conditions and can be quantified in blood. These circulating miRNA, which are very stable, are viewed as promising biomarkers for a number of CV diseases. The endothelial glycocalyx (EG) might be a promising biomarker of endothelial integrity. The EG is a negatively charged, organized mesh of membranous glycoproteins, proteoglycans, and associated plasma proteins. It is recognized as a contributor to the protection of the endothelium as well as the