Gender-specific effects of Notch3 in cardiac phenotype after moderate physical training

Abstract

Studies in mice have shown that the Notch3 protein plays a major role in the functional and structural plasticity of resistance arteries, angiogenesis, and contributes to the adaptation of these vessels to variations in loading conditions. Our aim was to determine whether gender is a factor of the cardiac phenotype of Notch3 KO mice in the basal state and in response to a volume overload. Two-month-old male and female C57Bl/6 J WT and KO Notch3 mice were used in a moderate training protocol on treadmill with increasing speed, in order to mimic the effort induced during cardiac rehabilitation. In basal conditions, KO mice are characterized by a low expression of VEGFR2 mRNA, leading to an arteriolar rarefaction ( P < 0.0002) without changes in capillary density regardless of gender. This results to a fibrosis in KO mice. However, gender differences are observed since males display cardiac hypertrophy ( P < 0.0001) while females have a decreased shortening fraction ( P < 0.0001). In training conditions, expression of sFlt1 mRNA increased in female Notch3 KO mice. Physical training increased the capillary density only in WT males ( P < 0.0332) whereas, it reduced the capillary density ( P < 0.0021) and induced cardiac fibrosis ( P < 0.0021) in Notch3 KO females. In addition, physical training reversed cardiac hypertrophy ( P < 0.0332) in male Notch3 KO, but has no major effect in the cardiac function of female Notch3 KO. This work highlights for the first time the gender-specific effects of Notch3 in the heart phenotype under control conditions and after moderate physical training.