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Early rescue of lymphatic function limits atherosclerosis progression in Ldlr−/− mice

  • Andreea Milasan
    Affiliations
    Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    Montreal Heart Institute, Montreal, Quebec, Canada
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  • Ali Smaani
    Affiliations
    Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    Montreal Heart Institute, Montreal, Quebec, Canada
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  • Catherine Martel
    Correspondence
    Corresponding author. Faculty of Medicine, Université de Montréal, Montreal Heart Institute, 5000, Belanger street, Room S5100, Montreal, Quebec, H1T 1C8, Canada.
    Affiliations
    Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    Montreal Heart Institute, Montreal, Quebec, Canada
    Search for articles by this author

      Highlights

      Early treatment with VEGF-C 152s:
      • Prevents lymphatic dysfunction and maintains the contractile capacity of the collecting lymphatic vessels throughout the whole atherosclerotic process;
      • Limits plaque buildup, then stabilizes plaque progression in Ldlr−/− mice.

      Abstract

      Background and aims

      Our previous data showed that 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. Concomitantly, we found that lymphatic transport can be restored in mice by systemic injections of a mutant form of VEGF-C (VEGF-C 152s), a growth factor known to increase mesenteric collecting lymphatic vessel pumping through a VEGFR-3-dependent mechanism in rats. In the present study, we aimed to determine whether and how early modulation of collecting lymphatic vessel function could restrain atherosclerosis onset and limit its progression.

      Methods

      Before the administration of a pro-atherosclerotic regimen, Ldlr−/− mice at 6 weeks of age were injected intraperitoneally with VEGF-C 152s or 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 first improved lymphatic molecular transport in 6-week-old Ldlr−/− mice and subsequently limited plaque formation and macrophage accumulation, while improving inflammatory cell migration through the lymphatics in HFD-fed mice. The contraction frequency of the collecting lymphatic vessels 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.

      Conclusions

      These results suggest that 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.

      Graphical abstract

      Keywords

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