1. Introduction

Endothelium has been described to present key roles in the vascular physiology: various endothelium-derived endogenous substances [1], namely contracting (endothelin, prostaglandin

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

F2a and thromboxane A2) and/or relaxing (prostaglandin I2 and nitric oxide, NO) factors [2, 3] can modulate blood vessel tone. These substances, known as endothelium-derived contracting factors (EDCF) or endothelium-derived relaxing factor (EDRF), can modify the vascular smooth muscle tone directly, acting on smooth muscle cells, or indirectly, by altering sympathetic transmission [4]. Nevertheless, when endothelium integrity and/or function is compromised, such regulation can be impaired. Indeed, evidence suggests that endothelial dysfunction (present an altered NO production and oxidative stress) may contribute to the pathogenesis of hypertension. As a consequence, an increase in peripheral vascular resistance occurs in conditions where endothelium is somehow injured. For example, endothelium dysfunction leads to the enhancement of contractile responses to vasoconstrictor agents [2, 5–8]. Nevertheless, in the literature, there are also innumerous other factors that can also influence endothelium function and, therefore, vascular responsiveness, such as tetrahydrobiopterin (BH4), sex hormones and gender, angiotensin, insulin, vascular endothelial growth factor, vitamin D, adiponectin, uric acid, lipids, oxygen-derived free radicals, aldosterone and epithelial sodium channels.

2.1. NO effects on vasodilation and endothelial dysfunction

reductase domain that convert nitrites to NO [9].

density lipoproteins.

NO is a well-known EDRF that induces vasodilation through the activation of soluble guanylyl cyclase in the vascular smooth muscle cells producing cyclic guanosine monophosphate (therefore, through the signaling pathway that can be represented as NO-cGMP/cGMP-dependent kinases). It is well accepted that the benefits of NO released from endothelium are compromised in vascular diseases and aging since there is a reduced amount of NO. However, evidence also show that the production of NO can be upregulated, for example, by estrogens, exercise and dietary factors and downregulated by oxidative stress, smoking, pollution and oxidized low-

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Moreover, when endothelium is dysfunctional, the vasodilation induced by endothelial mediators is impaired and it can even lead to vascular smooth muscle cells contraction. For instance, in aged subjects and in vascular diseases (essential hypertension and diabetes) when the production of NO is compromised, endothelium-dependent contractions are intensified.

NO is produced by three isoforms of NO synthase, presenting a more general distribution in the human body than that initially predicted: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). nNOS is constitutively expressed in central and peripheral nervous system contributing to regulation of blood pressure, smooth muscle dilation and vasodilation via peripheral nitrergic nerves. iNOS is expressed in several cell types and generates large amounts of NO, which is involved in the pathophysiology of inflammatory diseases, as regulatory effector molecule of the innate immune response and septic shock. eNOS is expressed mainly in endothelial cells and has several vasoprotective and anti-atherosclerotic effects as well as an important role in vascular tone and thus blood pressure regulation.

Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling and endothelial dysfunction in the vasculature. eNOS generates NO which results from the activity of two domains, the oxygenase domain that convert L-arginine to L-citrulline plus NO and the

As mentioned above, NO production from endothelium can be upregulated or downregulated by a number of factors of which vascular endothelial growth factor (VEGF) can upregulate eNOS. Interestingly, a chronic side effect of VEGF inhibitors is the occurrence of hypertension, suggesting a physiological role for VEGF in maintaining endothelial control of vasomotor tone [10–12]. In humans, in hypertension, VEGF inhibitors may cause increased production of

Acute and chronic increases in flow as well as the resulting augmentation in shear stress of the blood on the endothelial cells can be altered through Ca2+-dependent and Ca2+-independent pathways. It has been described that Ca2+-independent pathway can increase both the expression and activity of eNOS and thus the release of NO [17]. The role played by the endothelial cells to protect against thrombin and other platelet products by increasing the activity of eNOS has been demonstrated both in vitro [18–26] and in vivo [27]. Serotonin and adenosine diphosphate are mediators released by aggregating platelets, which may activate eNOS and increase NO production. When endothelium is absent/dysfunctional, vasodilation is no longer observed,

endothelin-1 [13, 14] and reduced vascular response to acetylcholine [15, 16].

In this chapter, the impact of endothelial dysfunction on vascular neurotransmission is debated with particular focus on adenosinergic and nitroxidergic system dynamics.
