Soluble Endoglin and Its Interaction with Adhesion Molecules in Patients with Thalassemia Intermedia

Endoglin (CD105) is an accessory protein of the transforming growth factor-β receptor system expressed on vascular endothelial cells. Mutations on the endoglin gene are associated with hereditary hemorrhagic telangiectasias (Osler-Weber-Rendu syndrome) and, thus, endoglin has been extensively studied in the context of this disease. Endoglin is highly expressed on endothelial cells in healing wounds, developing embryos, inflammatory tissues and solid tumors. It is a marker of activated endothelium, while its vascular expression is limited to proliferating cells. Previous studies have shown that the endothelial function is impaired in patients with Thalassemia Intermedia (TI). Oxidative damage resulting from hemolysis and iron load, leads to increased expression of the intercellular and vascular adhesion molecules-1 (ICAM-1 and VCAM-1) and impaired nitric oxide (NO) bioavailability. As endoglin plays a critical role in angiogenesis and dysregulation of its expression and/or activity has been implicated in multiple vascular diseases, we aimed to investigate the expression of endoglin and its correlation with factors of endothelial dysfunction in patients with TI. Thirty adult patients with TI were included in the study, while 20 healthy individuals served as controls. Soluble endoglin, soluble forms of adhesion molecules ICAM-1, VCAM-1, E and P-Selectins, thrombomodulin, von Willebrand factor, as well as NO and vascular endothelial growth factor (VEGF), were measured in patients and controls, by immunoenzymatic methods. The main results of the study are:

• levels of endoglin, E-selectin, thrombomodulin, VCAM-1, ICAM-1 and VEGF in patients with TI (5.5±0.4 ng/ml, 91.4±20.0 ng/ml, 48.8±16.5 ng/ml, 1413.7±176.1 ng/ml, 658.8±34.6 ng/ml and 619.1±227.8 pg/ml, respectively) were higher compared to controls (4.9±0.3 ng/ml, 10.3±2.2 ng/ml, 4.0±0.6 ng/ml, 328.3±43.8 ng/ml, 107.6±26.5 ng/ml, 81.3±58.1 pg/ml), (p<0.01),

• endoglin levels in patients with TI correlated positively with concentrations of ICAM-1 (r=0.760, p<0.003), VCAM-1 (r=0.520, p<0.05), E-Selectin (r=0.790, p<0.0020, P-Selectin (r=0.530, p<0.04), while these correlations were absent in normal individuals.

Angiogenesis is a highly coordinated process in which VEGF, endoglin and hypoxia inducible factor 1 (HIF-1) play a pivotal role by coordinating interaction between endothelial cells, extracellular matrix and the surrounding cells. Taking into assumption that endoglin is a protective-repair tissue protein, our findings support the hypothesis that patients with TI exhibit increased degree of angiogenesis and endothelial regeneration, which are probably compensatory mechanisms in response to tissue hypoxia and damage.