Vascular endothelium dysfunction

Deckert, V, Desrumaux, C., Athias, A., Duverneuil, L., Palleau, V, Gambert, R, Masson, D., Lagrost, L. (2002). Prevention of LDL alpha-tocopherol consumption, cholesterol oxidation, and vascular endothelium dysfunction by polyphenolic compounds from red wine. Atherosclerosis, 165, 41-50. 

In the recent review Carr et al. [54] considered potential antiatherogenic mechanisms of a-tocopherol and ascorbic acid. These authors concluded that these antioxidants are able to inhibit LDL oxidation, leukocyte adhesion to the endothelium, and vascular endothelial dysfunction. They also believe that ascorbic acid is more effective than a-tocopherol in the inhibition of these pathophysiological processes due to its capacity of reacting with a wide spectrum of oxygen and nitrogen free radicals and its ability to regenerate a-tocopherol. 

Dysregulation of the vascular endothelium has emerged as a critical component of most thrombotic disorders [10, 21]. Often without any anatomical sign of atherosclerosis, many cardiovascular diseases express a vasomotor abnormality termed endothelial dysfunction, indexed clinically as impaired endothelium-dependent vasodilation [31]. Although its mechanism is multifactorial, endothelial dysfunction is characterized by diminished vascular NO production and/or bioavailability [32]. The... 

A study has been undertaken to clarify whether glucocorticoid excess affects endothelium-dependent vascular relaxation in glucocorticoid treated patients and whether dexamethasone alters the production of hydrogen peroxide and the formation of peroxynitrite, a reactive molecule between nitric oxide and superoxide, in cultured human umbilical endothelial cells (7). Glucocorticoid excess impaired endothelium-dependent vascular relaxation in vivo and enhanced the production of reactive oxygen species to cause increased production of peroxynitrite in vitro. Glucocorticoid-induced reduction in nitric oxide availability may cause vascular endothelial dysfunction, leading to hypertension and atherosclerosis. 

Apart from being a vasodilator, nitric oxide is also a potent inhibitor of neutrophil adhesion to the vascular endothelium. This is due to the inhibitory effect of nitric oxide on the expression of adhesion molecules on the endothelial surface. The role of nitric oxide in protecting the endothelium has been demonstrated by studies that showed that treatment with nitric oxide donors protects against ischemia- and reperfusion-mediated endothelial dysfunction. 

Percutaneous coronary intervention (PCI) inevitably causes extensive denudation of the vascular endothelium at the stenosis site, In animal models of stent placement, re-endothelialization begins to occur in the first two to seven days postplacement, Full re-endothelialization of the stent takes three or four weeks, This process has been called stent passivation, It is thought that a similar or longer time course occurs in humans, although this has been difficult to quantify from the rarity of available autopsy specimens from patients poststent insertion (3), In animals, endothelial dysfunction is seen up to three months poststenting (4),... 

Fig. 3.2 Hey generates H2S that relaxes the vascular endothelium. The rate-limiting steps are the CBS and CGL in generation of H2S. The deficiency in CBS or CGL causes increase in Hey and leads to vascular dysfunction.

As the knowledge of the pathogenesis of atherosclerosis rapidly increases, it appears that an active vascular endothelium, smooth muscle cells, and blood-borne cells such as monocytes and macrophages all play active roles in the atherosclerotic disease process. Risk factors, such as elevated plasma levels of certain lipids, prooxidants, and cytokines, may contribute to the chronic activation/stimulation as well as to the damage of the endothelium and other vascular tissues (160). There is evidence that supports the hypothesis that it is not only pure cholesterol and saturated fats but rather oxidation products of cholesterol and unsaturated fats (and possibly certain pure unsaturated fats) that are atherogenic, possibly by causing endothelial cell injury/dysfiinction. Lipid-mediated endothelial cell dysfunction may lead to adhesion of monocytes, increased permeability of the endothelium to macromolecules, i.e., a decrease in endothelial barrier function, and disturbances in growth control of the vessel wall. 

All drugs that interfere with sympathetic autonomic activity, including diuretics, can potentially interfere with male sexual function, expressed as a failure of ejaculation or difficulty in sustaining an erection. Nevertheless, placebo-controlled trials have emphasised how common a symptom this is in the untreated male popialation (approaching sometimes 20-30%). It is also likely that hypertension itself is associated with an increased risk of sexual dysfunction since loss of NO production by the vascular endothelium is an early feature of the pathophysiology of this disease. Laying the blame on antihypertensive medication is probably... 

Another mechanosensor well-studied in the vascular endothelium is the primary cilia. Primary cilia, resembling rods covered by membranes, extend from the surface of the cells [129]. Nauli et al [130] have studied the role of vascular endothelial cilia by targeting polycystin-1, required for cilia function, and Polaris, required for their structure. Cells without functional cilia lack the ability to translate extracellular shear stress into intracellular calcium signaling and nitric oxide synthesis. The primary cilia are critical for the normal function of the endothelium, which certainly warrants further analysis into their role in valve dysfunction and CAVD. 

The vascular endothelium in its healthy state is antiatherogenic, antiproliferative, regulates vascular tone, and maintains blood flow. Diseases such as diabetes, atherosclerosis, hypertension, coronary artery disease, and stroke are associated with vascular endothelial dysfunction (VED). Under experimental conditions, administration of uric acid or nicotine or sodium arsenite for extended periods to rats produced VED by impairing the integrity of vascular endothelium and decreasing serum and aortic concentrations of nitrite/nitrate. The acetylcholine-induced endothelium-dependent relaxation was attenuated. Concurrent treatment of these rats with... 

There are cases when a dedicated CV telemetry study may be the best option to assess target liability concerns for BPs. These include the presence of the therapeutic target in the CV system (e.g., cardiac myocytes, vascular endothelium, or vascular smooth muscle) or the emergence of CV findings in nonclinical toxicity studies or clinical trials. For example, observation of cardiac dysfunction in patients treated with trastuzumab, a mAb for treatment of breast cancer, prompted the sponsor to perform a long-term telemetry study in the cynomolgus monkey in attempts to model the human cardiac dysfunction (Klein and Dybdal 2003). Likewise, a novel ADC based on trastuzumab was evaluated in a dedicated NHP telemetry study to evaluate potential target-mediated CV effects (Poon et al. 2013). 

HDL inhibits monocyte chemotaxis, inhibits the adhesion of monocyte and blood cell to vascular endothelium, inhibits endothelial dysfunction and apoptosis, inhibits LDL oxidation, inhibits complement activation, reduces platelet aggregability and coagulation, inhibits platelet activation, and inhibits factor X activation. HDL helps maintain endothelial integrity, facilitate vascular relaxation, stimulates the proliferation of EC and SMC, stimulates the synthesis of prostacyclin and natriuretic peptide C in EC, stimulates protein C and S activation, and may favor fibrinolysis. These functions are exerted by different components of HDL, this complexity emphasizes that changes in HDL functioning rather than plasma HDL-C levels determine the anti-atherogenicity of therapeutic alterations of HDL metabolism (reviewed in refs. 499 and 500). 

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