Abstract 19498: 4-D Light-Sheet Imaging and Moving-Domain Computation Reveal That Oscillatory Shear Index Mediates Endocardial Notch1b Signaling and Valve Development

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Introduction: Blood flow modulates valvulogenesis. The mechanotransduction underlying oscillatory shear index (OSI) and valve development in the outflow tract (OFT) remain poorly understood.

Hypothesis: We hypothesized that increased OSI promotes Notch-mediated valve formation in the OFT.

Methods and Results: Integrating 4-D light-sheet imaging with moving-domain computational fluid dynamics (CFD), we assessed changes in Notch1b activity in the OFT and ventriculobulbar (VB) valve formation in response to various hemodynamic modulations in transgenic Tg(fli:EGFP) zebrafish embryos. Isoproterenol-mediated increases in contractility, heart rate, and OSI promoted concomitant increased Notch1b activity in the OFT and hyperplastic VB valve leaflets, whereas metoprolol-mediated mild decreases in those hemodynamic parameters resulted in no effects on Notch1b activity and valve formation. EPO mRNA injection at the one-cell stage to increase viscosity resulted in both increased Notch1b activity and hyperplastic VB valve leaflets, whereas Gata1a morpholino oligonucleotide (MO) injection to reduce viscosity had no effects. Further, 2,3-butanedione monoxime (BDM) markedly decreased contractility, heart rate, and OSI, and was associated with attenuated Notch1b activity and VB valve development. Similarly, Tnnt2a MO injection completely inhibited contractile function, resulting in marked reduction in Notch1b activity and absence of VB valve leaflets.

Conclusions: Increased OSI in the OFT activates endocardial Notch1b signaling accompanied with VB valve development. Augmentation of OSI results in VB valve hyperplasia, whereas marked reduction in OSI results in VB valve underdevelopment. By integrating advanced optics with zebrafish genetics and developmental cardiac mechanics, we provide mechanotransduction insights into cardiac valve development.

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