VEGFA Stop-Gained Variant Deteriorates Cardiac Remodeling in Myocardial Infarction.

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Angiogenesis Research

Background:

• Vascular endothelial growth factor A (VEGFA) is essential for blood vessel formation in normal physiology and cardiovascular diseases.
• Alternative translation initiation from CUG codons produces mature VEGFA, a process targeted by certain genetic variants.
• The impact of stop-gained variants, which prematurely terminate CUG-initiated translation, on vascular health is not well understood.

Purpose of the Study:

• To investigate the functional consequences of a VEGFA stop-gained variant on cardiac vasculature.
• To model human VEGFA variants using a CRISPR/Cas9-generated mouse allele (Q150X).
• To assess the role of VEGFA dosage in cardiac homeostasis and after myocardial infarction (MI).

Main Methods:

• Generated a mouse model (Vegfa^Q150X/Q150) mimicking human stop-gained VEGFA variants using CRISPR/Cas9.
• Evaluated cardiac vasculature in homeostatic and acute myocardial infarction (MI) conditions.
• Employed immunofluorescence, light-sheet imaging, single-nucleus RNA sequencing, and transcriptomics/epigenomics to analyze cellular and molecular changes.

Main Results:

• Mice with the VEGFA Q150X variant showed reduced VEGFA levels (70% in homeostasis, 40% post-MI) but were viable.
• The Q150X variant led to functional deterioration in post-MI hearts.
• Endothelial cells exhibited increased hypoxia stress and inflammation; stressed cardiomyocytes and proinflammatory immune cells were enriched in the ischemic zone.

Conclusions:

• CUG-initiated translation significantly contributes to VEGFA production in ischemic hearts.
• VEGFA dosage is a critical determinant of the cellular microenvironment during ischemic injury.
• Targeting VEGFA translation may offer therapeutic strategies for cardiovascular diseases.