Maternal Fetal Medicine
Oral or Poster Presentation
Concurrent Session 1B - Placental Fetal Physiology
Introduction: Placentation and early fetal cardiovascular development may be linked. Tetracycline-inducible (Tet-On) genes can be selectively introduced into the placenta and switched on using doxycycline (Doxy). However, Doxy is an inhibitor of matrix metalloproteinase-1 (MMP-1) gene expression which promotes healthy placentation. High doses of Doxy lead to abnormalities or fetal loss. MMPs activate endothelin-1 (ET-1), a vasoactive peptide. Our objective is determining the effect of low-dose Doxy treatment alone on the heart-placenta axis. We hypothesize that no differences would be found in placenta structure, ET-1 levels or heart function with low-dose Doxy treatment.
Methods: Mice were treated from embryonic day 6.5 (E6.5) with feed containing Doxy (200mg/kg) (n=4 maternal mice) or control feed (n=3 maternal mice). Analysis of fetal heart dimensions, flow, and function by M-Mode and Doppler ultrasound assessment was performed on E12.5 and E16.5. Paraffin-embedded placentas sections were stained with H&E to analyze placental structure and CD31 for vascularity. ET-1 expression was assessed by Western blot and qRT-PCR in a single placental lysate from each pregnancy (n=7).
Results: Results: Maternal weight gain was less with fewer fetuses in Doxy-treated dams. Placental weight increased but fetal weight was not different. The Doxy group had diastolic dysfunction. Western Blot revealed no significant difference in ET-1 levels in placentas from control and doxy-treated dams (Doxy n=4, 3.56±0.70; Ctrl n=3, 5.17±0.52, p=0.14). ET-1 mRNA expression decreased in placentas from the Doxy group (Doxy n=7, 0.43±0.08; Ctrl n=4 0.94±0.16; p=0.0098) Comparison of MMP activity and analysis of placental structure using Image J between groups is in progress.
Conclusion: There were fewer fetuses with reduced maternal weight gain along with fetal cardiac dysfunction after low-dose maternal Doxy treatment. Analysis of MMP activity, ET-1 levels and placental ultrastructure and vascularity may yield further insights into mechanisms for these findings.
Funding: WCHRI Clinical Fellow Trainee Research Grant, WCHRI Innovation Grant