**4. Conclusion**

The bad ROS are turned into the good ones thus ameliorating their damaging effects [133].

Shear stress and various agonists also stimulate the production of other vasodilators, among

AA is liberated from membrane phospholipids by the action of Ca2+-stimulated phospholi-

functions. Three main complex enzymatic pathways of AA metabolism are the cyclooxygenase pathway, the cytochrome (CYP)-P450 pathway, and the lipoxygenase pathway; however, AA can be transformed into isoprostanes nonenzymatically by ROS [135]. Regarding vascular tone regulation, AA metabolites include a number of vasodilators and vasoconstrictors

belongs to the CYP-450 family and is highly expressed in endothelial cells and associated with cyclooxygenase (COX)-2 [115, 135–137]. Its vasodilator effects mainly involve binding to prostacyclin (IP) receptors and activation of adenylate cyclase increasing cAMP level in

lium-dependent vasodilation *in vivo* has often been questioned and its other effects, such as inhibition of platelet adhesion and aggregation, and reduction of oxidative stress [135, 139] might rather account for its vasculoprotective effects. Moreover, COX-2-derived PGI<sup>2</sup> might play a compensatory role for the decreased NO bioavailability [117, 118]. To this end, it must be noted that other prostanoids from the COX metabolic pathways also affect vascular tone: due to various metabolic pathways as well as various prostaglandin receptors coupled to different signaling pathways, they might either induce vasoconstriction or vasodilation [115, 135, 137–139]. It is the delicate balance between vasoconstrictors and vasodilators which enables normal functioning of healthy endothelium; in endothelial dysfunction, the effect of vasoconstrictive prostanoids predominates, predisposing to the development of hyperten-

dependent, flow-mediated vasodilation; by blocking eNOS (by L-NMMA) and COX (by more or less specific COX inhibitors), the role of non-NO-non-PGE-dependent vasodilation has unequivocally been confirmed not only in *in vitro* assays and in animal models but also *in vivo*

Many of endothelial mediators and signals are known to induce the hyperpolarization of VSMC [8, 130, 135, 136, 145, 146]: epoxyeicosatrienoic acids (EETs) produced in the CYP-450-

ions released from the endothelial cells via Kca channels, and direct transmission of endothelial cell hyperpolarization by myoendothelial gap junctions. Thus, EDHF comprises a variety of factors which activate various potassium channels: small (SKCa), intermediate, and

, endothelial hyperpolarization (EDH) accounts for endothelium-

O2

[133, 140], potassium

, and subsequently metabolized into biologically active eicosanoids with a variety of

have also been suggested to overtake the role of NO in the

, formed by prostacyclin synthase, which

as endogenous mediator of endothe-

O2

**3.2. Endothelium-dependent relaxations beyond NO: hyperpolarization**

which the derivatives of arachidonic acid (AA) play an important role.

settings of reduced NO bioavailability also in humans [134].

One of the most investigated AA metabolites is PGI<sup>2</sup>

VSMC and subsequent relaxation. Yet, the role of PGI<sup>2</sup>

sion, atherosclerosis, and various other diseases.

in various human vessels during resting [140–143] and exercise [144].

dependent metabolism of AA [135, 136]; the above mentioned H<sup>2</sup>

Indeed, increased levels of H2

14 Endothelial Dysfunction - Old Concepts and New Challenges

pase A2

[113–115, 135–138].

Besides NO and PGI<sup>2</sup>

By spreading throughout the vascular system and exerting pleiotropic functions, the endothelium could be regarded as one of the main players in cardiovascular physiology. The integrity of endothelium is crucial for vascular homeostasis and health. On the other hand, endothelial cells are susceptible to changes in blood composition and hemodynamic forces and as such vulnerable to developing endothelial dysfunction. Endothelial dysfunction nowadays is acknowledged a key initiating event in atherosclerosis, and connected to several pathological conditions and cardiovascular events. Accordingly, understanding endothelial function and dysfunction is crucial for recognition and treatment, or, optimally, for prevention of the development of cardiovascular diseases, the leading cause of death worldwide. To this end, it should be emphasized that the mechanistic studies on isolated vessels or on animal models cannot always be extrapolated directly to humans. Therefore, in spite of intensive investigations, additional studies to elucidate mechanisms of endothelial function and dysfunction are necessary to accomplish endothelium-targeted interventions.

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