Abstract 3945: Soluble Flk-1 and Soluble Tie-2, Endogenous Inhibitors of Endothelial Cell-specific Angiogenic Signals, are Increased in Serum of Patients with Metabolic Syndrome.
Introduction: Therapeutic angiogenesis with use of growth factors is an attractive treatment paradigm for coronary heart diseases. However, the presence of atherosclerotic risk factors such as diabetes mellitus and dyslipidemia perturbs angiogenesis and minimizes beneficial effects of the angiogenic therapy. These facts limit application of this therapy to patients with metabolic syndrome (MS), a constellation of multiple risk factors. Vascular endothelial growth factor (VEGF) and angiopoietin-1 regulate angiogenesis through their endothelial cell-specific receptors, Flk-1 (VEGF receptor-2) and Tie-2. Soluble forms of Flk-1 and Tie-2 (sFlk-1 and sTie-2) block interaction of VEGF/Flk-1 and angiopoietin-1/Tie-2, respectively, thus acting as endogenous inhibitors of angiogenesis.
Objectives: To dissect mechanisms of decreased angiogenic activity in MS patients.
Methods: We measured serum levels of angiopoietins, VEGF family of growth factors and their soluble receptors in 84 consecutive outpatients. These were divided into the patients with and without MS, according to the criteria of MS presented in Japan in April 2005. There were 63 MS patients [mean age 62.9 ± 13.7 (SD) years, 31 men and 32 women], and 21 non-MS patients (61.1 ± 9.45 years, 16 men and 5 women).
Results: Serum levels of VEGF, placental growth factor, angiopoietin-1 and angiopoietin-2 did not differ between the patients with and without MS. However, serum levels of both sFlk-1 and sTie-2 were significantly (p<0.01) increased in MS patients compared with non-MS patients. Increase in sFlk-1 was correlated with increase in body mass index, serum triglyceride, and fasting plasma glucose, and decrease in adiponectin levels. Multivariate stepwise linear regression analysis revealed that increase in triglyceride levels was the strongest independent predictor of sFlk-1 levels. In contrast, levels of a soluble form of Flt-1 (VEGF receptor-1), a non-specific VEGF receptor, did not differ between MS and non-MS patients.
Conclusions: sFlk-1 and sTie-2, endogenous inhibitors of VEGF and angiopoietin-1-dependent angiogenic signals in vascular endothelial cells, are increased in MS patients, implying a possible mechanism of decreased angiogenic activity in MS.