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Nitric Oxide and Vascular Disease
Endothelial dysfunction is a key component in the pathophysiology of cardiovascular disease (CVD) and is associated with classic CVD risk factors such as dyslipidemia, hypertension, metabolic syndrome, and diabetes. Moreover, endothelial dysfunction is one of the first clinically detectable alterations in the development of atherosclerosis, and it is a common mechanistic link between atherosclerosis risk factors and the development of the disease. The vascular endothelium, far from being an inert barrier between the blood and the vessel, plays a key role in vascular control and homeostasis. The endothelium participates in the regulation of vascular tone, delivery of nutrients, and removal of waste, as well as in inflammation, thrombosis, and coagulation. Thus, preserving endothelial function is critical for maintaining vascular health.
The secretion of autocrine and paracrine mediators by the endothelium accounts for many of its regulatory functions. The endothelium secretes both vasorelaxing and vasoconstricting factors, and it controls local angiotensin II activity. The main constricting factor produced by the endothelium is endothelin-1. Conversely, the main relaxing factors secreted by the endothelium are nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarization factors. Of all these factors, NO appears to be one of the most important for CVD, because reduced NO bioavailability is synonymous with endothelial dysfunction. When endothelial dysfunction occurs, a pathophysiologic state associated with increased expression of adhesion molecules, increased synthesis of proinflammatory and prothrombotic factors, increased oxidative stress, and dysfunctional regulation of vascular tone occurs.
Physiology of Nitric Oxide in the Vasculature
In 1980 Furchgott and Zawadzki showed that endothelial cells produce a signaling molecule capable of inducing vasodilation. Later, Ignarro and Furchgott demonstrated that this molecule was in fact NO. Since then, NO has been shown to be a signaling molecule involved in key pathways in the nervous, immune, and cardiovascular systems. NO is synthesized from the amino acid l -arginine by a group of enzymes called NO synthases (NOS) in a reaction that requires oxygen and nicotinamide adenine dinucleotide phosphate (NADPH).
Three NOS isozymes have been described: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The endothelium constitutively expresses eNOS. eNOS activity is regulated by intracellular Ca 2+ , in a Ca 2+ /calmodulin-dependent fashion. Other stimuli independent of Ca 2+ concentration are also capable of activating eNOS. One such stimulus is shear stress, which induces phosphorylation and activation of eNOS. Other stimuli capable of inducing NO synthesis in the endothelium are acetylcholine, bradykinin, thrombin, and adenosine diphosphate (ADP). However, although the predominate source of NO in the vasculature is from eNOS, there is also evidence that NO bound to circulating thiols might act as a NO reservoir. Furthermore, reduction of nitrite by oxidases could generate significant amounts of NO under hypoxic conditions.
NO release from endothelial cells has many effects in the vasculature. The most notable function of NO is to regulate vascular tone. eNOS activation by either shear stress or parasympathetic stimulation is the main initiator of this pathway. NO diffuses from the endothelium to the tunica media, where it activates smooth muscle guanylate cyclase. However, other sources of NO, such as nNOS, have been shown to regulate tone in large vessels and in the coronary vascular bed.
NO has a profound effect on circulating blood elements. NO inhibits platelet aggregation, adhesion, and activation. NO is also a key regulator of the inflammatory process by inhibiting leukocyte adhesion and migration into the vascular wall. Even though the mechanisms through which NO regulates inflammation are not fully understood, it is known that NO inhibits inflammatory cytokine production, which results in reduced expression of adhesion molecules on the endothelial surface. NO is also a potent inhibitor of vascular smooth muscle cell (VSMC) and adventitial fibroblast proliferation and migration, while also stimulating VSMC apoptosis. On the other hand, NO has the opposite effect on endothelial cells, by promoting endothelial cell proliferation and inhibiting endothelial cell apoptosis. NO has been shown to decrease matrix deposition as well as oxidation of low-density lipoprotein (LDL). Lastly, NO is a key mediator of angiogenesis. It is known that prostaglandin E 1 , vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietin all stimulate angiogenesis through NO-dependent processes.
Pathophysiology of Nitric Oxide in the Vasculature
Endothelial dysfunction has been documented in almost every condition associated with CVD. In humans, it has been observed in persons with hypertension, normotensive subjects with a family history of hypertension, smokers, passive smokers, and patients with dyslipidemia, diabetes mellitus, obesity, hyperhomocysteinemia, and inflammatory disease. All of these conditions are also characterized by an overproduction of reactive oxygen species (ROS). One key aspect of the pathobiology of NO in the vasculature is its close and intricate relationship with ROS.
Oxidative stress is defined as an imbalance between ROS production and antioxidant defenses, and it is a key contributor to endothelial dysfunction. Chronic and acute overproduction of ROS under pathophysiologic conditions is a hallmark of the development of CVD. The main sources of ROS in the vasculature are the NADPH oxidases (NOXs), xanthine oxidase, and the mitochondrial respiratory chain, all capable of producing superoxide (O 2 •- ). O 2 •- itself can be further metabolized to yield hydrogen peroxide and all other ROS. An array of enzymatic and low-molecular-weight antioxidant defenses exist to protect against the detrimental effects of ROS. The main enzymatic antioxidant defenses include superoxide dismutases (SODs), glutathione peroxidase, catalase, heme oxygenase, and peroxiredoxins. The main endogenous low-molecular-weight antioxidants are glutathione and thioredoxin.
Oxidative stress results in reduced NO bioavailability mainly by two mechanisms: decreased production of NO and rapid oxidative inactivation of NO. ROS can decrease NO production by inactivation of eNOS, which is susceptible to oxidative damage. NOX is capable of inducing eNOS uncoupling, a process that results in O 2 •- production from eNOS instead of NO. Oxidation of the eNOS cofactor tetrahydrobiopterin (BH 4 ) can further contribute to eNOS uncoupling. An increase in arginase activity, the enzyme that metabolizes l -arginine, can also result in a decrease in NO production. High arginase activity has been reported in animal models for hypertension, diabetes, and heart failure.
Oxidative stress has also been shown to decrease the activity of dimethylaminohydrolase, the enzyme that metabolizes asymmetric dimethylarginine (ADMA), hence leading to an increase in ADMA concentrations. ADMA can inhibit eNOS and contribute to eNOS uncoupling. In fact, ADMA has been established as an independent predictor for cardiovascular mortality. Finally, ROS can limit NO bioavailability owing to the rapid inactivation of NO via its fast reaction with O 2 •- to yield peroxynitrite (ONOO - ). This reaction is of great significance because ONOO - is a highly reactive molecule capable of further oxidative damage.
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