Abstract 13125: FOXO1/Notch Signaling Modulates Ambient Ultrafine Particle Exposure-Impaired Vascular Development
Introduction: Exposure to ultrafine particles (UFP, d < 0.1 μm), redox-active components of particular matter (PM2.5), promotes vascular inflammatory responses. Notch signaling in endothelial cells (EC) promotes differentiation and proliferation of vasculature. FOXO1, the dominant isoform of the forkhead box O subfamily (FOXO) in EC, interacts with Notch signaling via enhancing co-repressor clearance and assembly of activation complex during induction of Notch signaling. Whether a FOXO1/Notch signaling axis modulates UFP- impaired vascular development remains elusive.
Hypothesis: We hypothesized that UFP impairs vascular repair by attenuating Notch signaling via inhibition on FOXO1.
Methods and Results: Transgenic Tg(fli1:gfp) zebrafish at 3 days post fertilization (dpf) developed vascular regeneration at 3 days post amputation (dpa) of the tail, whereas exposure to UFP or treatment with ADAM10 inhibitor (inhibit Notch receptor activation to generate Notch intracellular cytoplasmic domain [NICD]) resulted in disrupted intersegmental vessels (ISV) and impaired tail regeneration (P < 0.05, n=20). Notch signaling was evidently visualized in the region of tail injury in the Notch responsive reporter fish Tg(tp1:gfp) crossed with Tg( flk1:mCherry) line at 3 dpa. UFP, ADAM10 inhibitor, and FOXO1 morpholino oligonucleotides (MO) micro-injection attenuated Notch activities at 3 dpa, respectively. NICD mRNA rescue partially restored Notch activity and vascular regeneration at 3 dpa, whereas combination of both NICD and FOXO1 mRNA rescue fully restored Notch activity and tail regeneration. As a corollary, UFP exposure induced a dose-dependent reduction in Notch reporter activity and FOXO1 mRNA expression in human aortic endothelial cells (HAEC). FOXO1 mRNA rescue restored Notch activity and Notch related gene expressions, including Dll4 and HES1(P < 0.05, n=3) in fish exposed to UFP.
Conclusions: UFP impairs vascular regeneration via Notch signaling. Notch/FOXO1 cooperation is implicated in promoting vascular development.
Author Disclosures: K. Baek: None. T. Beebe: None. Z. Ma: None. J. Gau: None. A. Saffari: None. C. Sioutas: None. R. Li: None. T. Hsiai: None.
- © 2016 by American Heart Association, Inc.