Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice

Epidermal growth factor receptor (EGFR) signaling contributes to aortic valve development in mice. Because developmental phenotypes in Egfr-null mice are dependent on genetic background, the hypomorphic Egfrwa2 allele was made congenic on C57BL/6J (B6) and 129S1/SvImJ (129) backgrounds and used to identify the underlying cellular cause of EGFR-related aortic valve abnormalities. Egfrwa2/wa2 mice on both genetic backgrounds develop aortic valve hyperplasia. Many B6-Egfrwa2/wa2 mice die before weaning, and those surviving to 3 mo of age or older develop severe left ventricular hypertrophy and heart failure. The cardiac phenotype was accompanied by significantly thicker aortic cusps and larger transvalvular gradients in B6-Egfrwa2/wa2 mice compared with heterozygous controls and age-matched Egfrwa2 homozygous mice on either 129 or B6129F1 backgrounds. Histological analysis revealed cellular changes in B6-Egfrwa2/wa2 aortic valves underlying elevated pressure gradients and progression to heart failure, includ...