The Potential of VEGF-C as a Therapeutic Target for Atherosclerosis Treatment
Yumna Furqan
Introduction: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, smooth muscle cell proliferation, cell apoptosis, necrosis, fibrosis, and local inflammation.2 Levels of plasma cholesterol, LDL cholesterol, and apolipoproteins are highly correlated with clinical atherosclerosis.4 VEGF-C (vascular endothelial growth factor-C) is a member of the PDGF/VEGF family that promotes angiogenesis and endothelial cell growth. VEGF-C is involved in the repair of injured myocardium and can serve as a marker in patients with suspected or confirmed cardiovascular disease.3 VEGF-C is expressed in embryonic tissues – endothelium of large placental vessels, cells in maternal decidua and syncytiotrophoblasts, and many tissue and organs of adults. 2 Recent studies have shown that targeted delivery of VEGF-C to pre-existing atherosclerotic lesions reverses lipid accumulation, reduces intimal cell death, and increases plaque stability.1 Methods: The F8 antibody specifically targets the extra domain A of fibronectin, an isoform that accumulates in inflamed tissues including atherosclerotic lesions. Extra domain A’s absence in steady-state renders it a suitable target to site-specifically deliver cytokines and hence they tested the ability of F8-VEGF-C conjugates to stabilize vulnerable lesions. Advanced lesions in the carotid artery of Apoe−/− mice were generated. To investigate the effects of VEGF-C on advanced atherosclerosis, Apoe−/− mice with pre-existing lesions were treated with F8-VEGF-C. Results: VEGF-C reduced the effects of atherosclerosis through two mechanisms: reducing endoplasmic stress and stimulating cholesterol efflux from smooth muscle cells. ER stress deregulates cholesterol metabolism in human hepatic cells by inhibiting 3-hydroxy-3-methyl glutaryl coenzyme A reductase-mediated cholesterol synthesis and by impairing ATP-binding membrane cassette transport protein A1 (ABCA1)-mediated cholesterol efflux.9 VEGF-C is associated with reduced levels of the transcription factor C/EBP (CCAAT-enhancer-binding proteins) Homologous Protein, an important trigger of endoplasmic reticulum stress. 7 VEGF-C favored cholesterol efflux in SMCs to a similar extent as the LXR (liver X receptor) agonist used as positive control, an observation that can at least in part be explained by increased expression of the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in response to VEGF-C. Neuropilin 1 and neuropilin 2 have been suggested to mediate some of the actions of VEGF-C through the ABCA1 transporter. Conclusion: Overall, VEGF-C lowers lipid content in intimal SMCs by two mechanisms: reducing endoplasmic stress and stimulating cholesterol efflux of smooth muscle cells. With further human studies, injection of VEGF-C can potentially become the primary treatment for atherosclerotic lesions in humans.
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