Contribution of PARP to endothelial dysfunction and hypertension in a rat model of pre‐eclampsia

Abstract

BACKGROUND AND PURPOSEUnder conditions of increased oxidative stress, such as pre-eclampsia and diabetes, overstimulation of PARP leads to endothelial dysfunction. Inhibition of PARP has been demonstrated to reverse the vascular dysfunction associated with diabetes in vivo. The present study was carried out to investigate the role of PARP in mediating the endothelial dysfunction associated with pre-eclampsia. EXPERIMENTAL APPROACHUteroplacental perfusion was surgically reduced in pregnant rats to produce the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia and the PARP inhibitor, PJ34, was administered either before or after surgery. Mean arterial BP and vascular function were measured in normal pregnant (NP) and both control and PJ34-treated RUPP rats. Mesenteric vessels from NP rats were incubated with either 3% RUPP or NP plasma alone or in combination with PJ34. Finally, immunohistochemical staining was carried out to measure nitrotyrosine (byproduct of peroxynitrite) immunoreactivity. KEY RESULTSRUPP rats were characterized by hypertension, fetal growth restriction and endothelial dysfunction when compared with NP rats. PJ34 administered in vivo before, but not after, surgery prevented the development of both endothelial dysfunction and hypertension. RUPP plasma-induced impaired vasorelaxation was prevented following co-incubation with PJ34 in vitro. Furthermore, the protective effect of PARP inhibition in vivo was accompanied by a reduction in nitrotyrosine immunoreactivity. CONCLUSIONS AND IMPLICATIONSPJ34 prevented the development of both endothelial dysfunction and hypertension and reduced vascular nitrotyrosine immunoreactivity, thus suggesting a role for oxidative-nitrosative stress/PARP activation in the aberration in both vascular and haemodynamic function in this rat model of pre-eclampsia. Abbreviations3% NPP, 3% normal pregnant plasma; 3% RP, 3% RUPP plasma; AOI, area of interest; BK, bradykinin; KPSS, potassium physiological salt solution; MABP, mean arterial blood pressure; NP, normal pregnant; PJ34, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide.HCl; PJ34-Post, PJ34 post-surgery; PJ35-Pre, PJ34 pre-surgery; PSS, physiological salt solution; Rmax, maximal relaxation; ROS, reactive oxygen species; RUPP, reduced uterine perfusion pressure; U46619, 9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2a

Vascular Dysfunction in Preeclampsia

“…Consistent with human studies, in the rat RUPP model, vessels from normal‐pregnant animals show impaired endothelium‐dependent vasodilatation following incubation with RUPP plasma . Experiments in both humans and rats have found that plasma‐mediated endothelial dysfunction is prevented by incubating vessels in the presence of a PARP inhibitor, suggesting a role for vascular dysfunction mediated by oxidative stress‐stimulated PARP activation .…”

Inhibition of Poly-(ADP-Ribose) Polymerase Protects the Kidney in a Canine Model of Endotoxic Shock

“…The most significant amelioration was seen on MAP, RBF and renal oxygen metabolism. It is reported that suppression of PARP could influence both vascular and hemodynamic function [15,25] by upregulating the CO, attenuating cardiomyocyte dysfunction and reducing the SVR [26,27,28]. Hans et al [29] presented that PARP-1 gene deletions prominently prevent the faltering of hemodynamic parameters in cardiac hypertrophy by directly effecting MMP-9 and TIMP-2 expression.…”

Drug Treatment of Hypertension in Pregnancy

“…In states of increased oxidative stress, such as diabetes, overstimulation of PARP leads to endothelial dysfunction and PARP inhibitors have been shown to be of benefit [62]. A recent investigation has demonstrated a protective effect of a PARP inhibitor, preventing the development of both endothelial dysfunction and hypertension, in a rat model of preeclampsia [62].…”

“…A recent investigation has demonstrated a protective effect of a PARP inhibitor, preventing the development of both endothelial dysfunction and hypertension, in a rat model of preeclampsia [62]. …”