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

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, culmi-

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

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)

nates in organ failure.

4 Endothelial Dysfunction - Old Concepts and New Challenges

marker of microvascular endothelial function [19].

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