Abstract 104: Early Rescue of Lymphatic Function Limits Atherosclerosis Progression in Ldlr -/- Mice

Abstract

Background: Lymphatic function impairment occurs before the onset of atherosclerosis in mice and is precociously associated with a defect in the propelling capacity of the collecting lymphatic vessels (LV). Lymphatic transport can be restored in mice by systemic injections of a mutant form of VEGF-C (VEGF-C 152s). In the present study, we aimed to determine whether and how early modulation of collecting LV function could restrain atherosclerosis onset and limit its progression. Methods: Ldlr -/- mice at 6 weeks of age were injected intraperitoneally with VEGF-C 152s or with PBS every other day for 4 weeks, fed on high fat diet (HFD) for an additional 8 weeks to promote plaque progression, and switched back on chow diet for 4 more weeks to stabilize the lesion. Results: Early treatment with VEGF-C 152s first improved lymphatic molecular transport in 6-week-old Ldlr -/- mice and subsequently limited plaque and macrophage accumulation, while improving inflammatory cell migration through the lymphatics in HFD-fed mice. The contraction frequency of the collecting LVs was significantly increased following treatment throughout the whole atherosclerotic process and resulted in enhanced plaque stabilization. This early and maintained rescue of the lymphatic dysfunction was associated with an upregulation of VEGFR3 and FOXC2 expression on lymphatic endothelial cells, albeit without modifying eNOS expression. Systemic injections with VEGF-C 152s did not initially alter mice cholesterol levels and lipoprotein profile. Unsurprisingly, total plasma cholesterol levels increased when the pro-atherogenic regimen was applied and an improved absorptive capacity of the mesenteric LVs was reflected by the presence of chylomicron remnants and lower levels of VLDL and LDL/IDL in the VEGF-C-treated group. VEGF-C 152s also did not significantly modulate HDL levels throughout the process. This indicates that VEGF-C-dependant stimulation of lymphatic function, independent of cholesterol levels, is responsible for subsequent atherosclerotic plaque buildup. Conclusions: Early treatments that specifically target the lymphatic contraction capacity prior to lesion formation might be a novel therapeutic approach for the prevention and treatment of atherosclerosis.