Proceedings of The Physiological Society
University College Dublin (2009) Proc Physiol Soc 15, C22
The role of plasma-mediated vascular dysfunction and PARP activation in pre-eclampsia
F. English1, S. K. Walsh1, E. J. Johns2, L. C. Kenny1
1. Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland. 2. Department of Physiology, University College Cork, Cork, Ireland.
Pre-eclampsia (PE) is associated with widespread maternal vascular dysfunction which is thought to be mediated by one or more circulating factors. Under normal physiological conditions, poly(ADP-ribose) polymerase (PARP) is cytoprotective. However under conditions of increased oxidative stress overstimulation of this enzyme leads to vascular dysfunction. Inhibition of PARP has been demonstrated to reverse the vascular dysfunction associated with diabetes in vivo . Thus the aims of the present study were to 1) investigate whether circulating factors induce vascular dysfunction in the reduced uterine perfusion pressure (RUPP) at model of PE, and 2) to examine the role of PARP in any observed changes in vascular reactivity in both rat and human vessels. On day 14 of pregnancy, animals destined for the RUPP experimental group were anaesthetised with isoflurane (2-5% inhalation) and a silver clip (0.203mm ID) was placed around the aorta (above the iliac bifurcation) to reduce uterine perfusion pressure by ~40% . Arterial blood was collected from both RUPP and normal pregnant (NP) rats and plasma aliquots stored at -80oC. Resistance vessels from both virgin and NP rats were incubated overnight in either 3% RUPP or NP plasma with or without the PARP inhibitor, PJ34 (3μM). Human omental arteries were incubated overnight with 3% NP or PET plasma, with or without the PARP inhibitors, PJ34 and DR2313 (3μM). Vascular function was assessed in response to the vasoconstrictor, U46619 and vasodilators, bradykinin and acetylcholine. Treatment of resistance vessels with RUPP plasma resulted in significantly impaired vasorelaxation (to both ACh (68 ± 6% vs. 87 ± 3%; p<0.05) and BK(36 ± 5% vs. 51 ± 3%; p<0.05)) in vessels from pregnant but not virgin rats. Furthermore, overnight incubation in RUPP plasma was necessary to induce this vascular dysfunction. Concomitant treatment with the PARP inhibitor, PJ34, abrogated the RUPP plasma-induced vascular dysfunction (ACh 81 ± 3% vs. 68 ± 7%; p<0.05) (BK 53 ± 3% vs. 36 ± 7%; p<0.05). Similarly, incubation of omental vessels from normal pregnant women in plasma from women with PE resulted in impaired relaxation to BK (45 ± 7% vs. 86 ± 3%; p<0.01). This impaired relaxation was reversed by co-incubation of the PET plasma with PJ34 (85 ± 2% vs. 45 ± 7%; p<0.05). In contrast, treatment with DR2313 did not significantly affect the impaired vasorelaxation induced following overnight incubation with PET plasma. The present study demonstrates that plasma-derived factors appear to mediate the vascular dysfunction documented in both the RUPP rat model of PE and the clinical condition. Furthermore, this work demonstrates a role for the overactivity of PARP in mediating this vascular dysfunction.
Where applicable, experiments conform with Society ethical requirements