Cardiac mural cells are rate-limiting for coronary vascularization after heart injury.

Limited angiogenic potential of coronary vascular endothelial cells (cVECs) poses a significant barrier to effective therapeutic revascularization after myocardial infarction (MI). However, the underlying mechanisms of restricted vascularization post-MI remain unclear. Here, we demonstrate that both reduced density and limited proliferation of mural cells result in inadequate mural cell coverage of coronary vessels, consequently impeding coronary vascularization within the MI heart. Our findings reveal that the cell cycle inhibitor phosphatase and tensin homolog (PTEN) is expressed in mural cells from both sham-operated and MI hearts. Conditional Pten deletion in mural cells enhances mural-derived cell (MDC) proliferation, increases coronary vascular density, promotes arteriogenesis, and improves cardiac function following MI. Furthermore, Pten deficiency upregulates chemokine C-X-C motif ligand 12 expression, which potentially reduces apoptosis in cVECs and MDCs and increases vascular density. These results identify cardiac mural cells as promising therapeutic targets for enhancing coronary angiogenesis and vascular remodeling after ischemic injury.