Endothelial KIT Signalling After Myocardial Infarction

• Applicant: Professor Dr. Kai Christoph Wollert
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530210503

Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication. Within days, a new vascular plexus develops in the infarct region, helping to limit the extent of scarring and left ventricular remodelling. Paracrine-acting growth factors play a central role in the regulation of angiogenesis after MI. In the previous project, we identified the monocyte- and macrophage-derived cytokine meteorin-like (METRNL) as a new angiogenic growth factor and high-affinity ligand for the endothelial KIT receptor. We found that both KIT(+) and KIT(-) endothelial cells (ECs) contribute to the capillarisation of the infarct region. In Metrnl-deficient mice, the expansion of KIT(+) ECs in the infarct region was selectively abolished and the animals developed severe heart failure. Our single-cell RNA sequencing (scRNA-seq) analyses identify KIT(+) ECs as a highly activated cell population after MI. We conclude that KIT labels an EC population that is crucial for proper wound healing. We postulate that KIT, along with a putative co-receptor (see below), induces the expansion and activation of this EC population. Both hypotheses shall be investigated in our project. In order to directly analyse the importance of the endothelial KIT receptor for angiogenesis and wound healing after MI, we have generated Kitfl/fl mice to selectively delete Kit in ECs before MI. Furthermore, we are planning sequential scRNA-seq analyses in Metrnl-deficient and EC-selective Kit-deficient mice to characterise the influence of METRNL and KIT on the composition of the EC compartment and to identify METRNL and KIT-activated target genes after MI. We are particularly interested in whether METRNL and KIT also influence infarct healing via angiocrine growth factors. Recent observations from our group indicate that not all KIT-expressing cell types are responsive to METRNL and suggest that there is a co-receptor rendering KIT(+) ECs METRNL-responsive. Indeed, in a bioinformatic analysis, we have discovered a co-receptor candidate in KIT(+) ECs that appears to be required, alongside KIT, for METRNL-mediated angiogenetic effects. We want to understand the putative interaction of METRNL and/or KIT with this co-receptor at the molecular level and to investigate the co-receptor’s importance for angiogenesis and wound healing after MI in a loss-of-function mouse model. Our investigations will enable a better understanding of cardiac EC heterogeneity and its importance for vascular repair after MI.

• DFG Programme: Research Grants