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Administration of the PARP inhibitor Pj34 ameliorates the impaired vascular function associated with eNOS(-/-) mice
Fred A English1, Fergus P McCarthy, Irene J Andersson
1Anu Research Centre, University College Cork, Cork, Ireland. fred@umail.ucc.ie
Insights
A PARP inhibitor, PJ34, improved uterine artery function and reduced blood pressure in a mouse model of pregnancy complications. This suggests PARP inhibition may protect against vascular dysfunction during pregnancy.
Area of Science:
- Reproductive biology
- Vascular physiology
- Pharmacology
Background:
- A healthy pregnancy relies on efficient uteroplacental circulation.
- Impaired uterine blood flow is linked to intrauterine growth restriction (IUGR) and preeclampsia (PE).
- Poly(ADP-ribose) polymerase (PARP) is implicated in oxidative stress-related vascular dysfunction.
Purpose of the Study:
- To investigate if a PARP inhibitor can mitigate vascular dysfunction in a mouse model with impaired endothelial nitric oxide synthase (eNOS(-/-)).
- To assess the impact of PARP inhibition on uterine artery function and blood pressure in eNOS(-/-) mice.
Main Methods:
- Utilized the eNOS(-/-) knockout mouse model, which exhibits vascular dysfunction and IUGR.
- Administered the PARP inhibitor PJ34 to eNOS(-/-) mice.
- Evaluated uterine artery function and systolic blood pressure at gestational day 17.5.
Main Results:
- eNOS(-/-) mice displayed impaired uterine artery function compared to controls.
- PJ34 administration prevented the impairment of uterine artery function in eNOS(-/-) mice.
- While eNOS(-/-) mice showed no altered systolic blood pressure initially, PJ34 treatment significantly reduced it compared to vehicle-treated eNOS(-/-) mice.
Conclusions:
- PARP inhibition, specifically with PJ34, protects uterine artery function in the context of eNOS deficiency.
- PARP inhibitors show potential therapeutic value for managing vascular dysfunction in pregnancy-related disorders like IUGR and PE.
Abstract:
A low-resistance/high-flow uteroplacental circulation is integral to a healthy pregnancy. Impaired flow in the uterine circulation is associated with intrauterine growth restriction (IUGR) and preeclampsia (PE). Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which has been associated with oxidative stress-induced vascular dysfunction. Using the endothelial nitric oxide synthase (eNOS(-/ -)) knockout mouse model, which features vascular dysfunction and IUGR, we tested the hypothesis that administration of a PARP inhibitor may ameliorate the vascular dysfunction associated with the eNOS(-/-) model. eNOS(-/-) animals were characterized by impaired uterine artery function when compared to controls. Administration of the PARP inhibitor PJ34 prevented this dysfunction. Gestational day (GD) 17.5 eNOS(-/-) mice did not exhibit altered systolic blood pressure when compared to control mice. However, treatment of eNOS(-/-) mice with PJ34 significantly reduced systolic blood pressure when compared to vehicle-treated eNOS(-/-). Administration of a PARP inhibitor protects uterine artery function in the face of eNOS(-/-) deficiency.
