Investigating the effects of VEGF overexpression on hyperglycemia accelerated atherosclerosis

Abstract

Diabetes mellitus is a chronic disease that can lead to severe complications, including an increased risk of cardiovascular disease. The underlying mechanisms that link diabetes to the development of vascular complications are not fully understood. Previous research from our lab has shown that hyperglycemic mice have accelerated atherosclerosis progression, in addition to increased arterial hypoxia, inflammation, and expression of hypoxia-inducible factor 1 alpha (HIF1-α), a transcription factor for genes involved in angiogenesis. However, impaired signalling through the HIF1-α pathway is evidenced by reduced vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2) and impaired neovascularization of the vasa vasorum – a microvascular network of capillaries that supply the walls of large arteries. We hypothesize that impaired VEGF expression contributes to the accelerated development of atherosclerosis in hyperglycemia. The objective of this study is to test a model of VEGF overexpression on atherosclerosis in hyperglycemia. A macrophage-specific inducible system for VEGF transgene overexpression was established using Cre-Lox technology. Triple mutant apoE-/-ROSA26-FLOXSTOP-VEGF164tg/0 CSF1R-iCREtg/0 mice were generated in a C57BL/6 background. Hyperglycemia was induced in half of the mice with streptozotocin. Macrophage-specific Cre recombinase was activated with tamoxifen at early and later stages of atherosclerosis, and hearts/aortas were harvested at 15 weeks of age. Lesion volume and expression of key factors in hypoxia-mediated angiogenesis were quantified. Our results demonstrate that overexpression of VEGF during early atherosclerosis progression reduces plaque volume and expression of the hypoxic marker, HIF-1α, in female mice. Understanding the effects of VEGF expression on lesion development will help delineate the biochemical pathways that link diabetes and cardiovascular disease. Validation of this mechanism may lead to novel and more effective strategies to treat/prevent diabetic cardiovascular disease.