Jacob Taylor
The Role of Neutrophils and Procoagulant Platelets in Intrauterine Growth Restriction (IUGR) in murine model of Hypertensive Disease of Pregnancy (HDP)
Mentor: Christian Con Yost, MD
Department: Pediatric Neonatology
Background: Hypertensive diseases of pregnancy (HDP) induce intrauterine growth restriction (IUGR) due to placental insufficiency. Elevated thromboxane A2 (TXA2) levels mediate maternal hypertension and IUGR. Cyclophilin-D (CypD) cues procoagulant platelet and neutrophil extracellular traps (NETs) formation. Neutrophils produce NETs, extracellular decondensed chromatin lattices containing antimicrobial proteins, to combat infection and tissue injury. The roles of procoagulant platelets and NETs in IUGR remain unknown. We hypothesized that platelet-specific Cyclophilin D knockout (CypDplt-/-) mice exhibit lower IUGR and placental NETs than wild-type (WT) mice in a model of HDP.
Methods: Pregnant CypDplt-/- and WT mice received a TXA2 analog (U46619) or vehicle control via micro-osmotic pumps implanted on embryonic day (E) 12.5. At E19, we measured fetal/placental weights and collected pup plasma. We assess plasma NET levels via the MPO-DNA ELISA, a surrogate for NET formation. Placental NETs and neutrophil levels were evaluated via Western blotting of placental homogenates and immunofluorescence for citrullinated histone H3 (citH3) and myeloperoxidase (MPO), respectively.
Results: Pup body weights show a decreasing trend in TXA2-treated CypDplt-/- compared to WT dams at E19. Western blotting indicated a trend towards reduced placental citH3 and MPO, suggesting decreased NETs and neutrophils in TXA2-treated CypDplt-/- IUGR placentas compared to WT IUGR placentas. No statistically significant differences were found between TXA2-treated CypDplt-/- and WT non-IUGR placentas dams, confirmed via immunofluorescence.
Conclusion: CypDplt-/- mice showed reduced IUGR and placental NETs in a murine HDP model. This suggests that procoagulant platelets trigger neutrophil activation and NET formation, contributing to HDP, placental insufficiency, and IUGR.
