Abstract 15285: Notch3 is Required for the Cardiac Adaptation to Hypertension
Background: The Notch3 receptor has a role in the integrity of resistance arteries by controlling the maturation of vascular smooth muscle cells (VSMC). Hypertension in Notch3 null mice (N3-/-) rapidly induced a heart failure. The mechanistic pathways being not defined, we hypothesize that alterations of the coronary tree secondary to Notch3 invalidation might trigger the development of heart failure in response to hypertension.
Methods: N3-/- and WT C57/Bl6J mice were used. At 11 week of age, WT and N3-/- mice were implanted with Alzet mini-pumps filled with Angiotensin 2 (Ang2, 1μg/kg/min) or NaCl for 28 days (n=15-23/ group).
Results: Normotensive N3-/- mice showed ventricular hypertrophy (+20%, p<0.001 vs WT) combined with defects of coronary artery tree including decrease in F-actin content in the media (-20%, p<0.05) and in arteriolar density (p<0.05). In response to Ang2, N3-/- mice were less hypertensive than the WT +Ang2 mice (157±9mmHg vs 184±7mmHg, P<0.05) but developed a more severe failing heart phenotype with lower shortening fraction (-12%, p<0.05), higher cardiac hypertrophy (+35%, p<0.05), and enhanced induction of inflammation markers [galectin-3 x3.5, p<0.01], higher signs of oxidative stress. This lack of adaptive response of the heart to hypertension was accompanied by major alterations of the coronary arteries including the absence of medial hypertrophy and decreased expression of F-actin in VSMC (-50%, p<0.01 vs WT +Ang2). Moreover the analysis of angiogenic signaling pathway, in N3-/- +Ang2, which combined the induction of Angiopoietin 2 mRNA (+70%, p<0.05) and the repression of VEGFa (p<0.05) was in favor of coronary artery destabilization.
Conclusion: Altogether, these data demonstrate that Notch3 activation in the VSMC of coronary artery plays a key role in the adaptation of the heart to Ang2- induced hypertension, and in turn in the development of heart failure.
Author Disclosures: H. Ragot: None. R. Merval: None. M. Baudet: None. E. Polidano: None. L. Fazal: None. C. Delcayre: None. C. Chatziantoniou: None. J. Samuel: None.
- © 2014 by American Heart Association, Inc.