{
  "abstract": "Introduction Coronary heart disease, leading to myocardial infarction (MI), is the largest cause of death globally. Following MI, heightened inflammation and fibrosis leads to pathological remodelling, cardiac dysfunction and ultimately heart failure. All current treatments are palliative, and the only cure is transplantation. Improved therapeutic approaches are thus required for promoting optimal healing, requiring both tissue restoration and environment conditioning through modulating immune and fibrotic responses. We have previously shown that VEGFC-C156S treatment stimulates lymphatic vessel growth in the infarcted heart and elicits immune cell trafficking correlating with functional improvement. Here, we investigated which specific immune cell populations are preferentially cleared following VEGFC-C156S-induced lymphangiogenesis and how their absence functionally contributes to a more optimal response post-MI.Methods Wild-type mice treated with PBS or VEGFC-C156S underwent permanent coronary ligation and single cell RNA sequencing was conducted on live CD45+ cells isolated from hearts 7 days post-injury. CD68-CreERT2; Arg1flox/flox mice were used to target Arg1 in macrophages by tamoxifen induction, and animals underwent permanent coronary ligation with serial echocardiography for functional analysis.Results We found that improved cardiac outcome post-MI following VEGFC-C156S treatment coincides, paradoxically, with clearance of what have previously been described as M2 or pro-reparative macrophages from the infarcted heart, marked by high and specific expression of Arg1. As ARG1 is upregulated in humans post-MI and increased expression is noted in heart failure patients, we sought to interrogate the role of Arg1 in macrophages following cardiac injury. Macrophage-specific knockdown of Arg1 resulted in improved ejection fraction and increased cardiac output post-MI, occurring during the timeframe of expected M1 to M2 macrophage polarisation. The significant improvement in overall cardiac function also aligned with increased survival, reduced cardiac strain and smaller infarct size indicating potential differences in scarring following Arg1-macrophage depletion.Conclusions Our results reveal a detrimental role of Arg1 in macrophages within the infarcted heart by promoting pathological fibrotic remodelling and challenge the traditional M1 vs M2 macrophage paradigm. Together, these data highlight the potential therapeutic value of targeting specific subpopulations of immune cells to optimise the immune environment and promote effective repair and maintenance of function post-MI.",
  "authors": [
    {
      "affiliations": [
        "University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Susanna Cooper"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Sarah Sigal"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Michael Weinberger"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Christophe Ravaud"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Adam Lokman"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Paul Riley"
    }
  ],
  "title": "37 VEGFC-stimulated lymphangiogenesis clears a pro-fibrotic macrophage population to improve cardiac outcome following myocardial infarction",
  "uid": "fc513a41-6024-5b63-9ca1-bcd63b129fcd"
}