VEGFA Stop-gained Variant Deteriorates Cardiac Remodeling in Myocardial Infarction [RNA-seq]

A sustained dosage of Vascular Endothelial Growth Factor A (VEGFA) is crucial for angiogenesis in both homeostasis and cardiovascular diseases. CUG-initiated alternative translation is a conserved mechanism for producing mature VEGFA. Genetic surveys have identified stop-gained variants predicted to prematurely terminate CUG-initiated translation without affecting ATG-initiated translation. However, the impacts of these variants on the vasculature in steady-state and disease conditions remain unknown. Here, we identified that homozygous mice carrying the stop-gained variant were viable. VEGFA dosage reduced to 70% in the Q150X homeostatic heart, with no significant alteration in cardiac function or vasculature. In the MI model, VEGFA dosage in Q150X was reduced to about 40% within the first-week post-infarction, leading to functional deterioration in the post-MI hearts. Significant changes in cellular composition were observed three days post-MI. In particular, endothelial cells in Q150X diverged into a state that showed higher level of hypoxia stress, an elevated inflammatory response, and increased extracellular matrix secretion. Additionally, we observed an increase of Nppb+ stressed cardiomyocytes in both 3 days post-MI and homeostasis. Finally, pro-inflammatory macrophages, neutrophils, and Cd8+T cells were enriched in the ischemic zone of Q150X hearts. CUG-initiated translation contributes significantly to the production of mature VEGFA in ischemic hearts. VEGFA dosage is critical in determining the cellular microenvironment during ischemic injury.