Abstract 19794: Notch3 Modulates the Cardiovascular Adaptation to Output-Overload
Introduction: The Notch3 receptor plays an important role in differentiation, migration and signal transduction of vascular smooth muscle cells (VSMCs). We recently showed that Notch3 signaling was essential for the coronary adaptation to pressure overload and in turn prevented decompensated acute heart failure (Ragot et al, Hypertension in press).
Hypothesis: Notch3 signaling was involved in cardiovascular remodeling induced by two models of output-overload: the physical exercise or pregnancy.
Methods: Male and female mice knocked out for the Notch3 gene (Notch3-/-) or Wild-Type (WT) mice were respectively submitted to treadmill physical-training program for 5 weeks or mated. Methods included echocardiography, qPCR, western-blot, immuno- and histo-morphometry.
Results: At baseline, Notch3-/- females exhibited similar cardiac alterations that males including arteriolar rarefaction (-60%, p<0.001) and increased oxidative stress. Pregnancy induced a decrease in shortening fraction in Notch3-/- females (-25%, p<0.01 vs post-partum WT). Interestingly, a microvascular adaptation occurred with increase in the relative capillary density (+25%, p<0.05 vs Notch3-/-). By contrast, moderate physical training did not alter cardiac function in both Notch3-/- and WT males but led to an increase in F-actin content in the coronary artery media arteries and in capillary density (+12%, p<0.05) in the WT mice after training only, whereas these parameters were not increased in the Notch3-/- mice. The analysis of the angiogenesis pathways revealed an increased expression in the anti- angiogenic soluble receptor, sFLT1, in the Notch3-/- mice after training (+40%, p<0.05 vs WT+training) whereas it was not induced by the pregnancy in the Notch3-/- females.
Conclusions: Altogether, these data suggest that the Notch3 signaling pathway could mediate unique effect according to cardiac output stimuli and/or gender which may be due to unique modulation of sFLT1 expression.
Author Disclosures: H. Ragot: None. S. Guinemer: None. C. Delacroix: None. I. Da Costa: None. E. Polidano: None. R. Merval: None. C. Chatziantoniou: None. J. Samuel: None.
- © 2016 by American Heart Association, Inc.