Circulating levels of VEGF-C are closely associated with dyslipidemia and atherosclerosis

Circulating levels of VEGF-C are closely associated with dyslipidemia and atherosclerosis

Shuichi Ura1, Hiromichi Wada1, Shuji Kitaoka2, Noriko Satoh-Asahara3, Takahiro Horie4, Koh Ono5, Tomohide Takaya1, Rieko Takanabe-Mori1, Masaharu Akao6, Mitsuru Abe1, Tatsuya Morimoto7, Toshinori Murayama4, Masayuki Yokode4, Masatoshi Fujita8, Akira Shimatsu9, Koji Hasegawa1.

  1. Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  2. Health Evaluation Center, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  3. Division of Diabetes Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  4. Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Hospital, Kyoto, Japan.
  5. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  6. Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  7. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
  8. Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  9. Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

American Heart Association Scientific Sessions 2012 (Los Angeles, USA), 2012/11/03-07 (Talk).

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.