Abstract 11747: Circulating Levels of Vascular Endothelial Growth Factor-C are Closely Associated with Dyslipidemia and Atherosclerosis

Abstract

Background: The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. Vascular endothelial growth factor-C (VEGF-C), a homologue of the VEGF family, plays a pivotal role in lymphangiogenesis. Circulating levels of both VEGF-A and VEGF-C are elevated in sera from obese subjects. However, relationships of VEGF-C with atherosclerotic risk factors and atherosclerosis are unknown.

Methods and Results: We determined circulating levels of VEGF-A and VEGF-C in 423 consecutive subjects not receiving any drugs. After adjusting for age and gender, VEGF-A levels were significantly and more strongly correlated with the body mass index (BMI) and waist circumference than VEGF-C. Conversely, VEGF-C levels were significantly and more closely correlated with metabolic (e.g., fasting plasma glucose, hemoglobin A1c, immunoreactive insulin, and the homeostasis model assessment of insulin resistance) and lipid parameters (e.g., triglycerides, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C)) than VEGF-A. Stepwise regression analyses revealed that independent determinants of VEGF-A were the BMI and age, whereas strong independent determinants of VEGF-C were age, triglycerides, and non-HDL-C. In apolipoprotein E-deficient mice fed a high-fat-diet (HFD) or normal chow (NC) for 16 weeks, levels of VEGF-A were not significantly different between the two groups. However, levels of VEGF-C were significantly higher in HFD mice with advanced atherosclerosis and marked hypercholesterolemia than NC mice. Immunohistochemistry revealed that the expression of VEGF-C in atheromatous plaque of the aortic sinus was significantly intensified by feeding HFD compared to NC, while that of VEGF-A was not. Within plaque areas, there were abundant cells expressing LYVE-1, a marker of lymphatic endothelium, while cells expressing CD31, a marker of vascular endothelium, were detected only in the surface of plaque.

Conclusions: These findings demonstrate that VEGF-C, rather than VEGF-A, is closely related to dyslipidemia and atheroslerosis.