Role of Endotheliam in Vascular Complecation of Diabetes

                    Coronary artery, cerebrovascular and peripheral vasculardisease, are the principal causes of morbidity and mortality in type 2diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy.Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. Coronary artery, cerebrovascular and peripheral vascular disease are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Role of endothelium are described as follows.(38)

1)  Vasoregulation

The integrity of endothelium is needed to maintain the balance between vasodilation and vasoconstriction, and so preserve a sufficient vascular diameter for the satisfactory perfusion of the cardiovascular system. The endothelium is responsible for the short term regulation of this vascular tone. It produces vasodilatator substances, such as nitric oxide (NO) (which was previously called endothelium-derived relaxing factor (EDRF)), prostacyclin (PGI2) and endotheliumderived hyperpolarizing factor (EDHF). It also produces vasoconstrictor substances, such as endothelin-1, thromboxane A2 (TXA2) and prostaglandin H2 (PGH2). This vasoregulation is under the control of biochemical and mechanical stimuli. (31)

2)  Nitric oxide (NO)

Endothelium is essential for the relaxation of the isolated rabbit aorta in response to acetylcholine, the biological role of the endothelium and of NO has been extensively investigated in both animals and humans. NO is the best characterized and probably the most important vasodilator. NO is produced in response to a variety of stimuli by the oxidation of L-arginine by the NADPH-dependent enzyme, nitric oxide-synthase (NOS). Its production leads to physiological vasodilation and the relaxation of smooth muscle cells. This effect is mediated by protein G.

There are three isoforms of NOS, all of which transform L-arginine into nitric oxide and L-citrulline; eNOS (endothelial NOS), iNOS (inducible NOS), and nNOS (neuronal NOS). Two of them (eNOS and nNOS) are calcium-dependent. The Enos is located in the plasmalemma caveola of endothelial cells, close to caveolin-1, a protein that inhibits the enzyme activity of eNOS. The nitric oxide acts on smooth muscle cells by stimulating guanylate cyclase and by increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). The cGMP decreases the intracellular Ca2+ concentration causing vasorelaxation.(32)
Nitric oxide also inhibits platelet aggregation by a mechanism dependent on cGMP, having an antithrombotic effect. Finally, NO also inhibits the proliferation of smooth muscle cells, the synthesis of adhesion molecules, and antagonizes endothelin-1 (ET1) . Nitric oxide has a low molecular weight, diffuses rapidly and has a very short half life (a few seconds). It is thus an ideal tool for adapting the vasculature to changes in blood flow and allows instant changes in arterial diameter to cope with blood flow and shear stress.

3)  Prostacyclin
                 Another major vasodilator is prostacyclin, which is produced from arachidonic acid by the enzymes cyclooxygenase (COX) and prostacyclin synthase. Its release may be stimulated by bradykinin and adenine nucleotides. Prostacyclin acts by stimulating adenylate cyclase and by increasing intracellular cyclic adenosine monophosphate (cAMP). Like nitric oxide, prostacyclin is a potent vasodilator with a short half life, and acts in both the systemic and pulmonary circulations. Finally, prostacyclin plays a key role in the interaction between the endothelium and platelets by limitating the development of thrombi.(35)

4)  Endothelium-derived hyperpolarizing factor (EDHF)

                  Hyperpolarization of the underlying smooth muscle cells hence vasorelaxation. This diffusible relaxing and hyperpolarizing substance, distinct from nitric oxide or prostacyclins and designated endothelium-derived hyperpolarizing factor (EDHF), is secreted by the endothelium, and contributes to endothelium-dependent relaxations by opening K+/ATP dependent channels in the vascularsmooth muscle.(34)