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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