Kindlin-3 Promotes Angiogenesis via Notch Signalling and Is Crucial for Functional Recovery Postmyocardial Infarction

Angiogenesis is crucial for minimising ischemic injury postmyocardial infarction (MI), making it a significant target for cardioprotective therapies. While Kindlin-3 has been linked to angiogenesis in breast cancer, its specific function in the context of MI remains largely unexplored. Although Kindlin-3 has been implicated in breast cancer-related angiogenesis, its role in MI remains underexplored. This study investigates the role of Kindlin-3 in promoting angiogenesis, a process critical for cardiac recovery following MI. The study demonstrated a significant upregulation of Kindlin-3 in cardiac microvascular endothelial cells (CMECs) in mice post-MI. Overexpression of Kindlin-3, achieved through cardiotropic adeno-associated virus serotype 9 (AAV9) with the endothelial-specific promoter Tie2, enhanced myocardial angiogenesis, improved cardiac function, decreased cardiomyocyte apoptosis and reduced fibrosis. In vitro, Kindlin-3 overexpression promoted CMECs proliferation, migration, tube formation and the expression of angiogenesis-related genes. Conversely, Kindlin-3 knockdown exerted opposite effects. Mechanistically, Kindlin-3 activated the Notch signalling pathway, as its effects were abrogated by the Notch inhibitor DAPT and β1 integrin knockdown. This study identifies Kindlin-3 as a novel enhancer of angiogenesis and suggests its potential as a therapeutic target for myocardial repair.