P720Notch3 is an important mediator of cardiac adaptation to pressure overload

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Notch3, a receptor expressed in vascular smooth muscle cells (VSMC) and pericytes, has a key role in the integrity of resistance arteries by controlling the maturation of VSMC and the arterial differentiation. The goal of the study was to decipher the role of Notch3 in the normal heart and in the response to pressure overload.

To reach our objectives, we used adult male C57Bl/6J mice lacking expression of the Notch3 gene (N3-/-). Hypertension was induced by continuous infusion of Angiotensin II (AngII) for 28 days (1μg/kg/min) in WT and N3-/- mice (n>13). The analysis combined with echocardiography analysis, mRNA quantification, western-blot, immuno- and/or histo-morphometry.

In basal conditions, N3-/- mice exhibited cardiac hypertrophy (+20%, p<0.001 vs Wild Type, WT) combined with defects at the structure of coronary artery as evidenced by decreased F-actin content in the media (-20%, p<0.05) and decreased density of arterioles (p<0.05).

The AngII -induced Hypertension is lower inN3-/- mice (-20%, p<0.05 vs WT +AngII). Despite this blunted systemic effect, N3-/- mice developed a more severe heart failure (HF) compared to WT+AngII mice with lower shortening fraction (-20%, p<0.01), higher cardiac hypertrophy (+35%, p<0.05), and enhanced markers of fibrosis and inflammation [induction of galectin-3 (x3.5, p<0.01)]. The results in N3-/- +AngII mice, which combined the induction of Angiopoïetin 2 mRNA (+70%, p<0.05) and the repression of VEGFa (p<0.05) are in favour of coronary artery destabilization. Interestingly, coronary vessels did not show medial hypertrophy and this lack of adaptive response to hypertension was accompanied by a decreased expression of F-actin and SM actin mRNA (-50%, p<0.01). Moreover a treatment by Notch3 antisens oligonucleotides (ON) of WT +AngII mice impair coronary artery network as suggested by Angiopoïetin 2 induction (p<0.05 vs WT+AngII+ scrambled ON).

Altogether, we provide lines of evidence that alterations of Notch3 signaling pathway in the coronary arteries might play a role in the occurrence of HF in response to chronic increase in blood pressure.

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