**1.1. Endothelial heterogeneity**

Although stemming from the same ontogenetic origin, to fulfill different metabolic and functional demands of tissues, the endothelial cells of different tissues exhibit distinct phenotypic and morphologic characteristics, accounting for its huge molecular and functional heterogeneity.

Endothelial heterogeneity could also be explained by the diversity of the vessel networks it is part of, namely arteries, veins, and capillaries which all serve different functions. While the endothelium of arteries and veins forms a continuous layer, it can be continuous, fenestrated, or discontinuous in capillaries, directing endothelial permeability and thus the degree of the filtration and reabsorption in the corresponding tissue. The representative tissues with the continuous non-fenestrated type of endothelium include the brain, the skin, the lung, and the heart; the continuous fenestrated type is found in tissues exhibiting extensive transcapillary transport: exo- and endocrine glands, the intestine mucosa, and the kidney glomeruli, whereas the prototype of the discontinuous endothelium are sinusoids in the liver and bone marrow vascular beds [1]. Endothelial cells of certain capillary beds, concomitantly with the adjacent tissue cells form specialized structures such as the blood-brain barrier composed of the brain capillary endothelial cells and the adjacent astrocytes, or special communications between maternal endothelial cells of the spiral arteries and fetal trophoblast cells in placenta [6].

While the thin capillary walls (of 0.2 μm order of magnitude) are composed only of endothelial cells anchored in their basal lamina (and surrounded by pericytes), in larger vessels, endothelium is part of the much thicker vascular wall. The latter comprises also the beneath lying vascular smooth muscle cells (VSMC) of arteries and veins, respectively, and the perivascular cells including macrophages and mesenchymal cells from the vessel adventitia.

It has been appreciated that the endothelial lining of arteriolar vascular beds primarily affects vascular tone and thus vascular resistance regulation, adjusted to tissue demands. Capillary endothelium in turn mainly determines water and solute passage into the tissues, whereas the one in the postcapillary venules directs vascular permeability and blood cell trafficking, being more involved in immune and inflammatory processes governing tissue repair and angiogenesis [7]. Therefore, apart from inter-endothelial cell junctions influencing capillary permeability, mutual communication of endothelial cells with other elements of the vascular wall importantly contributes to vascular homeostasis [8].

The vast heterogeneity of the endothelium of arteries and veins could additionally be explained by significantly different physiological and physical conditions to which endothelial cells of various vascular beds are exposed, such as blood pressure, shear stress, and pulsatility. Hemodynamic forces significantly impact endothelial structure and function: compared to ellipsoid morphology and coaxial alignment under the conditions of laminar flow, cell morphology and alignment change drastically in the settings of turbulent flow and at vessel bifurcations, all predisposing to atherogenicity [9, 10].

Endothelial cells therefore exhibit a wide range of plasticity, from alterations in the expression of various membrane receptors and adhesion molecules, changes in their morphology and shape, their mitogenic potential and even their potential to migrate or transit into different cell types (endothelial-to-mesenchymal transition) [3, 11].

#### **1.2. Endothelial dysfunction**

blood elements and the adjacent cells. Developmentally, it arises from mesoderm via the differentiation of hemangioblasts and angioblasts [3]. However, other cell lineages, such as adipose lineage and mesenchymal cells, can transdifferentiate into endothelial cells even in

Besides presenting a mechanical barrier between the blood and the tissues, the endothelium is actively involved in various processes, including the regulation of vascular tone, maintaining blood fluidity, and enabling proper hemostasis when needed, in leucocyte trafficking, inflammation, wound repair, and angiogenesis, and, therefore, is of crucial importance for vascular homeostasis. As it metabolizes and releases many physiologically active substances that by acting in auto-, para-, and endocrine manner, govern the above physiological processes, it

Although stemming from the same ontogenetic origin, to fulfill different metabolic and functional demands of tissues, the endothelial cells of different tissues exhibit distinct phenotypic and morphologic characteristics, accounting for its huge molecular and functional

Endothelial heterogeneity could also be explained by the diversity of the vessel networks it is part of, namely arteries, veins, and capillaries which all serve different functions. While the endothelium of arteries and veins forms a continuous layer, it can be continuous, fenestrated, or discontinuous in capillaries, directing endothelial permeability and thus the degree of the filtration and reabsorption in the corresponding tissue. The representative tissues with the continuous non-fenestrated type of endothelium include the brain, the skin, the lung, and the heart; the continuous fenestrated type is found in tissues exhibiting extensive transcapillary transport: exo- and endocrine glands, the intestine mucosa, and the kidney glomeruli, whereas the prototype of the discontinuous endothelium are sinusoids in the liver and bone marrow vascular beds [1]. Endothelial cells of certain capillary beds, concomitantly with the adjacent tissue cells form specialized structures such as the blood-brain barrier composed of the brain capillary endothelial cells and the adjacent astrocytes, or special communications between maternal endothelial cells of the spiral arteries and fetal trophoblast cells in placenta [6].

While the thin capillary walls (of 0.2 μm order of magnitude) are composed only of endothelial cells anchored in their basal lamina (and surrounded by pericytes), in larger vessels, endothelium is part of the much thicker vascular wall. The latter comprises also the beneath lying vascular smooth muscle cells (VSMC) of arteries and veins, respectively, and the perivascular

It has been appreciated that the endothelial lining of arteriolar vascular beds primarily affects vascular tone and thus vascular resistance regulation, adjusted to tissue demands. Capillary endothelium in turn mainly determines water and solute passage into the tissues, whereas the one in the postcapillary venules directs vascular permeability and blood cell trafficking, being more involved in immune and inflammatory processes governing tissue repair and angiogenesis [7]. Therefore, apart from inter-endothelial cell junctions influencing capillary permeability, mutual communication of endothelial cells with other elements of the vascular

cells including macrophages and mesenchymal cells from the vessel adventitia.

wall importantly contributes to vascular homeostasis [8].

adulthood [4, 5].

heterogeneity.

might justified be called an endocrine organ.

2 Endothelial Dysfunction - Old Concepts and New Challenges

**1.1. Endothelial heterogeneity**

Being directly exposed to intravascular milieu, it is obvious that the composition of blood and the (patho)physiological conditions strongly affect endothelial cells, in terms of mediating signals which directly target their surface and activate numerous intracellular signaling pathways. During our life span, we are exposed to a variety of risk factors and toxic and noxious stimuli from the external environment (including air pollutants, tobacco smoke, chemicals from food, radiation, different eating habits in terms of high salt, sugar or saturated fatty acids intake, etc.) which strongly impact endothelial cells and their functions. As such, endothelial cells are constantly being challenged by changing internal environment to which they adapt more or less successfully. As long as their adaptive capacity in terms of maintaining homeostasis between vasoconstrictors and vasodilators reflecting vascular tone regulation; anti- and procoagulant activity reflecting hemostatic processes; anti- and pro-inflammatory mediators affecting the inflammatory response, and pro- and antiangiogenic factors affecting new vessel formation, remains in physiological limits, one might consider the endothelium to be healthy. However, the delineation between health and disease is not easy to define. When the maladaptive patterns overweigh, endothelial dysfunction issues what leads to disease [12].

Although the mostly exposed clinical sign of endothelial dysfunction is impaired endothelium-dependent vasodilation, endothelial dysfunction on a broader scale encompasses a pro-inflammatory, proadhesive, procoagulant, and proliferative state predisposing to atherosclerosis [13]. Multiple mechanisms have been involved in the development of endothelial dysfunction, connected to alterations in glucose and lipid metabolism, insulin resistance, obesity, dyslipidemia, hyperhomocysteinemia, altered hormone and cytokine secretion, imbalance in the autonomic nervous system activity, arterial hypertension, etc. Oxidative stress is acknowledged to play a central role in the development of endothelial dysfunction; moreover, oxidative stress has been appreciated as one of the main factors involved in normal aging, which imminently is also associated with endothelial dysfunction [14]. Although the severity of endothelial dysfunction might differ between vascular beds, independent studies have shown correlations between endothelial dysfunction in different vascular beds [13, 15]. Therefore, endothelial dysfunction can be regarded as a systemic disorder: as tissues and organs depend on proper vascularization and an adequate supply of nutrients and removal of waste products, the dysfunctional endothelium not only predisposes to the development of cardiovascular diseases (atherosclerosis, hypertension, peripheral arterial disease, stroke, etc.) but also to a wide range of other diseases, including metabolic (diabetes, obesity), inflammatory, rheumatoid, oncology, and degenerative diseases, and in the worst scenario, culminates in organ failure.

function, with particular emphasis on its genetic background and senescence, its involvement in inflammation and hemostasis, and its adaptation to various environmental challenges are

Endothelium at a Glance

5

http://dx.doi.org/10.5772/intechopen.81286

Electron microscopy combined with various labeling techniques has enabled an insight into the endothelial structure. Along the arterial tree, the shape of endothelial cells varies from predominantly flat in arteries and capillaries to even cuboidal in high endothelial venules, a special type of postcapillary venules [1, 7]. As endothelial cells are challenged by diverse extracellular stimuli from their environment on a spatial and temporal basis, various signaling pathways finally culminate in (post)transcriptional modifications and thus marked alterations of the phenotype. In addition, some site-specific properties of endothelium are epigenetically determined. Using DNA microarray analysis, distinct gene patterns between large vessel and microvascular endothelial cells, as well as between blood and lymphatic endothelial cells have been shown [26]. While large vessels express several genes involved in the biosynthesis and remodeling of extracellular matrix (fibronectin, various collagens, osteonectin), microvascular endothelial cells abundantly express genes coding for basement membrane proteins (laminin, various integrins, CD36). In addition, microvascular endothelial cells were shown to express higher levels of transcripts encoding proteins involved in trafficking of circulating blood cells and pathogens which enables pathogens and immune cells to migrate to target tissues [26]. Interestingly, data suggest that the artery-vein identities of endothelial cells are established before blood circulation begins [26]. Recent findings on the organotypical differentiation of

**2. Endothelial function depends on its structural and molecular** 

microvascular beds are extensively presented elsewhere [3, 27].

due to transcellular vascular leakage of macromolecules [29].

ing receptor-dependent and receptor-independent transcytosis [30].

**2.1. On endothelial permeability, inter-endothelial cell junctions, and caveolae**

Given the pivotal role of the microvascular endothelium in supplying tissues with nutrients and oxygen, endothelial integrity is crucial for tissue-fluid homeostasis. While basal permeability mainly governs water and solutes transport across the capillary wall of a healthy endothelium, the term inducible (or induced) permeability refers to alterations in endothelial permeability associated with inflammation and occurs predominantly at the site of postcapillary venules [1]. The latter occurs as a consequence of endothelial cell retraction and intercellular gap formation by a variety of agonists (histamine, serotonin, bradykinin, substance P, vascular endothelial growth factor (VEGF)) [28], or according to more recent speculations,

In general, microvascular endothelial structure directs the capillary dynamics: fluids and small solutes (less than 3 nm) move passively across the endothelium mainly via paracellular transport mechanisms or transcellularly by simple diffusion (nonpolar substances and gases) whereas larger macromolecules are transported by transcellular mechanisms, includ-

extensively given in the following book chapters.

**characteristics**

Accordingly, understanding the physiology of the endothelium is of crucial clinical importance, and there is an ongoing search for potential strategies to postpone or at least ameliorate endothelial dysfunction and disease progression, either in terms of drugs application or avoiding the known risk factors; even more, when timely treated, endothelial dysfunction might be reversible [13]. To this end, additional methodological tools have to be accomplished in order to timely detect potential endothelial dysfunction. In spite of huge effort put in mechanistic studies performed on animal models and cell cultures, the exact tool to specifically reveal endothelial dysfunction clinically is missing and, at the moment, is far from being optimal. Various molecules have been used as surrogate markers of endothelial function, including soluble vascular adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF), angiopoietin-2 [16], adipocytokines [17], microparticles [18], and several more; yet, they mostly lack the sensitivity and specificity, and are often too robust to detect subtle preclinical changes. Also functional studies to assess endothelium, such as measurement of arterial intima-media thickness or flow-mediated dilation (FMD), offer just a raw estimation of endothelial function. As proper organ functioning strongly depends on microcirculation, particular attention should be given to this vascular bed also in the clinics. An interesting observation when tracing the microcirculation *in vivo* is that it exhibits typical oscillations of distinct frequencies [19, 20]. It has been suggested that each of them could reflect particular aspect of vascular tone regulation: low frequency oscillations have shown good correlations with the endothelial component of vascular tone regulation and therefore could be used as a marker of microvascular endothelial function [19].

Endothelium represents a therapeutic potential: many newer drugs targeting endothelium either its surface and the corresponding membrane receptors, or intracellular targets affecting various signaling or metabolic pathways or directly its genome, are being developed and tested on the level of preclinical and clinical studies. In addition, independent studies have also shown that many classical cardiovascular drugs, such as angiotensin receptor antagonists, calcium (Ca2+) antagonists, angiotensin converting enzyme (ACE) inhibitors, and beta adrenergic blockers, and other drugs (antidiabetic agents, sulfonylurea, etc.) apart from acting via their established mechanisms also exert positive actions connected directly or indirectly to endothelium [21–23]. Yet, keeping in mind the huge heterogeneity of endothelial cell phenotype, one must not forget that therapy affecting endothelium should be targeted to specific vascular beds. In the last time, endothelium-targeted nanomedicine has evolved as a promising new model to deliver drugs directly into the endothelial cells [24]. Last but not least, exercise has long been appreciated as one of the most efficient measures to improve endothelial (dys)function in various ways: increasing nitric oxide (NO) bioavailability; induction of reactive oxygen species (ROS) scavenging enzymes [25]; affecting the sympathetic nervous system; and increasing the number of endothelial progenitor cells (EPCs) to list just a few.

In the subsequent sections of the chapter, basic concepts of endothelial (patho)physiology, relevant for the book, will briefly be addressed. More detailed information on endothelial (dys) function, with particular emphasis on its genetic background and senescence, its involvement in inflammation and hemostasis, and its adaptation to various environmental challenges are extensively given in the following book chapters.
