Endothelial Function and Behçet Disease

Behçet disease (BD) is an inflammatory disorder characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. Behçet disease is recognized as a multisystem vasculitis; vascular involvement is a prognostic factor that has been reported in 20% to 30% of the cases. Genetic, environmental, and immunological factors have been implicated. Endothelial dysfunction (ED) is also considered to play an important role in the pathogenesis of vasculitis and thrombosis in BD. Vascular involvement affects veins and arteries of all sizes and is more frequent and has a more severe course in young males. Several markers can be used to evaluate ED and vascular involvement in BD (eg, mean platelet volume, neutrophil–lymphocyte ratio, red cell distribution width, g-glutamyl transferase activity, and uric acid levels). However, these routine markers can be affected by hypertension, diabetes mellitus, metabolic syndrome, abnormal thyroid function, hepatic dysfunction, malignancy, respiratory disease, and medication. Ideally, such markers should not be influenced by these factors and should be widely used, reproducible, and noninvasive. The ED is also assessed by flow-mediated dilatation (FMD), arterial stiffness (AS), carotid intima–media thickness as well as high-sensitivity C-reactive protein (hsCRP), total homocysteine (tHcy), asymmetric dimethylarginine (ADMA), soluble thrombomodulin, E-selectin, vascular endothelial growth factor (VEGF), and endocan levels. The FMD is mainly influenced by nitric oxide (NO) from endothelial cells. Increased AS may be attributed to ED and inflammation associated with BD. The hsCRP reflects systemic inflammation and is related to ED. These findings as well as coagulation and fibrinolytic abnormalities may contribute to ED in BD. Other factors have been implicated in the ED process in BD such as increased low-density lipoprotein (LDL) oxidation and production of antibodies against oxidized LDL (oxLDL). The NO bioavailability is decreased in patients with BD. It has been reported that inflammatory processes increased NO production, but patients with BD had significantly lower NO levels with respect to controls. However, increased plasma ADMA (an endogenous inhibitor of NO synthase [NOS]) levels and decreased plasma NO levels have been reported in patients with BD. Inhibition of NOS by ADMA and oxidant/antioxidant imbalance may contribute to decreased bioavailability of NO in BD. Elevated tHcy levels may increase the susceptibility to vascular complications in patients with BD. Mean plasma tHcy levels were elevated in patients with BD and correlated well with the degree of endothelial damage. It was concluded that hyperhomocysteinemia may be an independent risk factor for venous thrombosis. Vascular endothelial growth factor is a potent mitogen for vascular endothelial cells and has also been regarded as a marker for ED. Inflammation is a stimulus for VEGF production and its levels are elevated in patients with BD. Endothelial cell-dependent arterial dilatation is significantly impaired in BD as shown by high-resolution ultrasound. Vascular endothelial growth factor may stimulate the formation of new vasa vasorum and may play a role in vessel wall damage in BD. Vascular endothelial growth factor can also act as a proinflammatory cytokine by increasing endothelial permeability and mediating the recruitment of circulating leukocytes into vascular inflammatory lesions via upregulating endothelial adhesion molecules and chemokine expression. We reported that patients with BD had significantly higher serum levels of endocan (a candidate endothelial immunoinflammatory marker), and these levels correlated positively with CRP, erythrocyte sedimentation rate, and BD activity. Serum levels of endocan were higher in patients with systemic involvement. We also showed that patients with psoriasis vulgaris had significantly higher serum levels of endocan, suggesting a link with another inflammatory condition. In this issue of Angiology, Ozoguz at al report that ED, as demonstrated by impaired brachial artery FMD and elevated ADMA levels, is a feature of BD even in patients without prominent vascular involvement. Based on these results, elevations in ADMA may contribute to ED in BD.