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Endothelial cell migration involves three major mechanisms, namely, chemotaxis, the directional migration toward an increasing gradient of soluble chemoattractants; haptotaxis, the directional migration toward an increasing gradient of immobilized ligands; and mechanotaxis, the directional migration generated by mechanical forces (). Endothelial cell migration during angiogenesis is the integrated result of these three mechanisms. Typically, chemotaxis of endothelial cells is driven by growth factors such as VEGF and basic fibroblast growth factor (bFGF), whereas haptotaxis is associated with increased endothelial cell migration activated in response to integrins binding to ECM components (, ). Because of their location at the inner surface of blood vessels, endothelial cells are constantly in contact with shear stress, which contributes to the activation of migratory pathways.
Endothelial dysfunction precedes the development of both the insulin resistance syndrome and atherosclerosis. Peripheral endothelial dysfunction, at the arteriolar and capillary levels, arises through a complex interplay of genetic and environmental factors and leads to a multifaceted metabolic disturbance comprising insulin resistance and the other features of the insulin resistance syndrome. Thus, this syndrome is a marker of peripheral endothelial dysfunction and plays a major role in atherogenesis but has little direct metabolic impact. The coexistence of central and peripheral endothelial dysfunction explains the observed association between atherosclerotic vascular disease and insulin resistance syndrome. This hypothesis could offer new insights into several clinical observations. First, it may be proposed that not all patients with coronary heart disease have an insulin resistance syndrome phenotype, because this syndrome is not an obligatory precursor of large-vessel atherogenesis, but rather a marker of peripheral endothelial dysfunction. However, subjects with peripheral endothelial dysfunction, such as those with diabetes or poor skeletal muscle capillarization, will be more likely to generate the insulin resistance syndrome phenotype, which accelerates endothelial dysfunction and atherogenesis in the large vessels. It is recognized, however, that additional local factors such as shear stress and rates of cholesterol deposition are likely to play important roles in restricting plaque formation to specific sites (). In summary, we propose that peripheral endothelial dysfunction is the principal cause of insulin resistance and insulin resistance syndrome.
Individuals with atherosclerosis exhibit both endothelial dysfunction and impaired insulin action. The endothelium plays an important role in the regulation of hemostasis, blood flow, maintenance of vascular architecture, and mononuclear cell transmigration-all of primary significance in atherogenesis. The endothelium also transports small molecules, macromolecules, and hormones such as insulin and degrades lipoprotein particles. Might endothelial dysfunction contribute to the individual components of the insulin resistance syndrome? Endothelial cells express the cognate insulin receptor (IR), which belongs to a family of membrane-bound receptors with intrinsic tyrosine kinase activity, whose ligands include growth factors such as insulin-like growth factor-1, vascular endothelial growth factor, platelet-derived growth factor, and epidermal growth factor. In addition to its crucial metabolic actions, insulin plays a critical role in the maintenance of physiological endothelial function through its ability to stimulate NO release via a cascade of signaling that involves activation of the PI3K-Akt axis and the downstream serine phosphorylation of endothelial NO synthase (eNOS) (). In addition to its NO-dependent vasodilatory actions, insulin stimulates endothelial release of the vasoconstrictor ET-1, as suggested by increased insulin vasodilatory effects in humans under ET-1 receptor blockade. Thus, insulin has multiple opposing hemodynamic actions, the net effect of which on blood pressure is negligible in normal individuals. Insulin resistance is characterized by specific impairment in PI3K-dependent signaling pathways, whereas other insulin-signaling branches, including Ras/mitogen-activated protein kinase-dependent pathways, are unaffected (). In addition, metabolic insulin resistance is usually paralleled by a compensatory hyperinsulinemia to maintain euglycemia. Thus, consequent hyperinsulinemia in insulin-resistant states will overdrive unaffected mitogen-activated protein kinase-dependent pathways. In the endothelium, decreased PI3K signaling and increased mitogen-activated protein kinase signaling in response to insulin may lead to decreased production of NO and increased secretion of ET-1, a characteristic of endothelial dysfunction. Indeed, insulin-resistant patients have elevated plasma ET-1 levels, and hyperinsulinemia increases ET-1 secretion in humans (, ). Pharmacological blockade of ET-1 receptors (ET-A isoform) improves endothelial function in obese and diabetic patients but not in lean, insulin-sensitive subjects. Endothelial dysfunction might also play a causal role in the development of insulin resistance. Insulin can relax resistance vessels and increase blood flow to skeletal muscle. Insulin acts on the vasculature in three discrete steps to enhance its own delivery to muscle/fat tissues (): Relaxation of resistance vessels to increase total blood flow (), relaxation of precapillary arterioles to increase the microvascular exchange surface perfused within the skeletal muscle, i.e. microvascular recruitment (), and promotion of the transendothelial transport of insulin itself (). Indeed, insulin resistance is associated with functional disturbances of the coronary circulation. Conversely, insulin infusion improves coronary flow, even in the setting of type 2 diabetes mellitus and coronary artery disease. Thus, such an imbalance between production of NO and secretion of ET-1 leads to decreased blood flow, which worsens insulin resistance. The reciprocal relationship of insulin resistance and endothelial dysfunction has been a subject of excellent review ().
The endothelium plays a key role in the pathogenesis of coagulation disorders in infectious diseases, although the precise mechanisms are not yet clear in some cases. The endothelium is involved in both bacterial and non-bacterial infections and is important for the initiation and regulation of hemostasis. The loss of the endothelium barrier and vascular leakage play a central role in the pathogenesis of hemorrhagic fever viruses in general. This can be caused either directly by the viral infection and damage to the vascular endothelium or indirectly by a dysregulated immune response resulting in an excessive activation of the endothelium. Disruption of the vascular endothelial barrier occurs in two severe disease syndromes, dengue hemorrhagic fever and hantavirus pulmonary syndrome. Both viruses cause changes in vascular permeability without damaging the endothelium. In the leaky vascular endothelium seen in dengue severe syndrome (DSS), various mechanisms that have been considered include immune complex disease, T-cell-mediated reactions, antibodies cross-reacting with the vascular endothelium, enhancing antibodies, complement and its products, various soluble mediators including cytokines, selection of virulent strains, and viral virulence; but the most favoured are enhancing antibodies and memory T cells in a secondary infection that results in a cytokine “tsunami.” Whatever the mechanism, the vascular endothelium is ultimately targeted (making it a battlefield), leading to this severe disease syndrome. Extensive recent work has been done using endothelial cell monolayer models to understand the pathophysiology of the vascular endothelium during a dengue virus infection, and the results may help in understanding the pathogenesis of DHF[Dengue Hemorrhagic Fever] /DSS (). Understanding the dynamics between viral infection and the dysregulation of the endothelial cell barrier will help us to define potential therapeutic targets for reducing disease severity (). Given the above data, it is conceivable that the therapeutic correction of endothelial dysfunction may lead to an improvement of prognosis in patients with PAD, cardiovascular diseases, stroke, chronic kidney failure, cancer or infectious disease. However, scant data are available on this topic, and most of the conclusions that can be drawn are highly speculative. There is, therefore, virtually no available substance able to specifically target the endothelium (Fig. ).