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

S. K. Walsh, F. A. English, I. P. Crocker, E. J. Johns, L. C. Kenny

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    BACKGROUND AND PURPOSE Under 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 APPROACH Uteroplacental 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 RESULTS RUPP 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 IMPLICATIONS PJ34 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. © 2012 The British Pharmacological Society.
    Original languageEnglish
    Pages (from-to)2109-2116
    Number of pages7
    JournalBritish Journal of Pharmacology
    Issue number7
    Publication statusPublished - Aug 2012


    • endothelial dysfunction
    • PARP
    • peroxynitrite
    • pre-eclampsia
    • reduced uterine perfusion pressure


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