Physiopathology of Vascular Endothelium

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The endothelial cells are flattened by intraluminal hydrostatic pressure, and show a wide cytoplasm with a central nucleus and, frequently, a nucleole. The cytoplasm contains the Weibel-Palade bodies, which are the depot of von Willebrand factor (vWF).

The endothelium produces a variety of mediators, such as nitric oxide (NO), prostanoids, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), and vWF.

The release of endothelium-derived relaxing factors (EDRFs) must be considered. These factors include, in addition to NO and prostacyclin, the endothelium-derived hyperpolarizing factor (EDHF), not yet fully identified, which may play a role, especially in smaller vessels. The importance of these relaxing factors is supported by the fact that endothelium-dependent vasodilatation is usually used as an easily reproducible and accessible parameter to test endothelial function in various conditions, such as T1DM and T2DM.

Endothelial dysfunction can be defined as the loss of normal vascular endothelium properties (e.g., alteration of protein synthesis, increased vascular tone and permeability, acquisition of prothrombotic and antifibrinolytic properties).

Definition of the Problem

In human T1DM, impaired endothelium-dependent vasodilatation has been reported in the absence of clinical signs of vascular complications. However, in well-controlled diabetics without albuminuria no alteration of endothelium-dependent vasodilatation has been reported. This is probably true also for T2DM. Whereas elevation of both vWF and its propeptide could indicate acute perturbation, elevated vWF levels alone may reflect chronic endothelial cell activation.

Impaired endothelium-dependent vasodilatation may be due to reduction of EDRF production, increase in EDRF inhibition, alteration in diffusion of EDRFs from the endothelium to the underlying smooth muscle cells, reduction of smooth muscle cell responsiveness to EDRFs, and increase in the production of endothelium-derived constricting factors (EDCFs), most likely prostanoids [1]. Impaired endothelium-dependent vasodilatation in T1DM correlates with duration of disease, glycemic control, and small-vessel disease.

Patients with high plasma levels of t-PA, PAI, vWF, and endothelin have an adverse cardiovascular prognosis. In particular, increased plasma vWF levels are detectable in patients with microalbuminuria, but not in those with early, uncomplicated, and well-controlled T1DM, or in those with early diabetic retinopathy. Nevertheless, the initial phase of vascular endothelium damage, defined by the term endothelial perturbation, which refers to a reversible dysfunction of the endothelial cells, is revealed by a simultaneous increase in circulating levels of vWF and t-PA that exceed 2 SD above control values. The combined determination of vWF and t-PA may be a specific and sensitive index of endothe-lial cell alteration, since vWF may also originate from platelets, and t-PA is also secreted by endothelial cells. vWF is considered an available marker of endothelial dysfunction. A prospective study showed that increased plasma vWF levels started about 3 years before the onset of microalbuminuria in adult patients with T1DM.

Pathogenesis of Endothelial Dysfunction

Poor glycemic control is the major factor responsible for the developing diabetic complications. However, despite meticulous metabolic control, 10 to 15 percent of patients develop renal complications after 20 years of diabetes duration. The mechanism of the progression of nephropathy is not completely understood. There is some evidence for the potential role of genetic factors in the development of diabetic kidney disease.

There is also evidence that all patients with diabetes will develop minimal retinopathy by 20 years after the onset of the disease. Vascular endothelium is a primary target of the altered glycemic metabolism in T1DM. High glucose concentrations may alter, either directly or indirectly, the antiatherogenic and antithrombotic properties of the vascular endothelium, through the formation of advanced glyco-sylation end products (AGEs) and reactive oxygen species (ROS), thus setting the stage for the ensuing development of vascular complications. Increased ROS may represent a single mechanism of induction, linking elevated glucose concentrations and three major biochemical pathways involved in the diabetic damage. Several parameters, such as vWF or prorenin, have been found to be associated with the development of microangiopathy independently from glycemic control in limited studies in children.

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