Distinct characteristics of circulating vascular endothelial growth factor-a and C levels in human subjects.

Hiromichi Wada,Shuji Kitaoka,Koji Hasegawa,Mitsuru Abe,Rieko Takanabe-Mori,Masaharu Akao,Noriko Satoh-Asahara,Shuichi Ura,Tatsuya Morimoto,Masayuki Yokode,Masatoshi Fujita,Akira Shimatsu,Takahiro Horie,Toshinori Murayama,Koh Ono,Tomohide Takaya,Marc Tjwa

doi:10.1371/journal.pone.0029351

Abstract

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. On the other hand, vascular endothelial growth factor-C (VEGF-C) plays a pivotal role in lymphangiogenesis. Circulating levels of 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. We determined circulating levels of VEGF-A and VEGF-C in 423 consecutive subjects not receiving any drugs at the Health Evaluation Center. 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. Furthermore, 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. In conclusion, these findings demonstrate that VEGF-C, rather than VEGF-A, is closely related to dyslipidemia and atherosclerosis.

Highlights

Obesity plays a major role in the development of dyslipidemia, hypertension and many other sub-clinical abnormalities that contribute to the atherosclerotic process and onset of cardiovascular events [1,2]
Levels of Vascular endothelial growth factor-A (VEGF-A) is positively correlated with body mass index (BMI), and this correlation is apparently disconnected from insulin sensitivity [8]
Serum levels of vascular endothelial growth factorC (VEGF-C), but not those of VEGF-A, were significantly higher in HFD than normal chow (NC) mice (Figures 2G and H). These findings indicate that VEGF-C, rather than VEGF-A, is closely related to advanced atherosclerosis with marked hypercholesterolemia induced by HFD in apoE-deficient mice

Summary

Introduction

Obesity plays a major role in the development of dyslipidemia, hypertension and many other sub-clinical abnormalities that contribute to the atherosclerotic process and onset of cardiovascular events [1,2]. The mechanisms that lead from obesity to atherosclerosis and cardiovascular events are not fully understood. It is widely accepted that adipose tissue development involves adipogenesis and angiogenesis [3]. It has been reported that VEGF-A accounts for much of the angiogenic activity of adipose tissue [5]. Circulating levels of VEGF-A are elevated in overweight and obese subjects [7]. A population-based cross-sectional study revealed that circulating VEGF-A levels have only a minor impact on the development of atherosclerosis [9]

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Results

Conclusion