Introduction
Myocardial infarction (MI) is the leading cause of heart failure, affecting ~1–3% of the global adult population (1). Lymphangiogenesis and neovascularisation are key regenerative mechanisms in the heart post-MI and both are known to be augmented by vascular endothelial growth factor (VEGF-C) (2-4). However, clinical studies using VEGF-C have proven problematic, including requirements for repeated invasive dosing (5-6). Identifying dual regulatory mechanisms of both vascular and lymphatic activation, including those downstream of VEGF-C, presents an exciting approach for future therapeutic strategies post-MI.
Hypothesis
Pathways that regulate endogenous vascular and lymphatic coronary regeneration after MI are co-ordinated in a spatial and temporal fashion.
Aims
- To study single nuclei and spatial transcriptomics data from the human heart to identify genes activated in both vascular and lymphatic EC post-MI.
- To define the mechanisms through which VEGF-C signalling mediates both neovascularisation and lymphangiogenesis post-MI.
Methods and Results
Aim (i). Informatics analysis of single nuclei RNAseq (7) and spatial transcriptomics data (in-house and (5)) identified 14 differentially expressed genes upregulated in both vascular and lymphatic endothelial cells (EC) in patients with acute MI versus the healthy heart. Aim (ii). Mice were administered VEGF-C or PBS at 0-, 2-, 4- and 6-days post-MI and hearts collected at 7-days for bulk RNA-sequencing (2). Eighteen genes were identified as activated downstream of VEGF-C. For each aim, 3 genes were selected for experimental validation (ongoing) based on; average Log2 fold change, literature assessment of function, and reproducibility in human MI data (for Aim ii).
Conclusion and Future Studies
We have identified genes with a potential regenerative role in acute MI via co-regulation of lymphatic and vascular EC responses, or as downstream molecular regulators of VEGF-C-mediated regeneration. Validation using immunofluorescence staining in human control heart and acute MI (n=8-10) is ongoing and will be followed by functional assessments in vitro and in vivo. Identification of novel targets that regulate both coronary angiogenesis and lymphangiogenesis after MI may enhance myocardial repair and prevent progression to heart failure.