Abstract
Background: Peroxisome proliferator-activated receptor-γ (PPAR-γ), a nuclear receptor expressed in placental tissue plays a seminal role in pregnancy. We aimed to 1) investigate the effect of PPAR-γ antagonism during uncomplicated pregnancy in rats 2) investigate the role of PPAR-γ activation during complicated pregnancy using the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia (PE). Methods: On gestational day (GD)11, a miniosmotic pump was inserted into the peritoneal cavity of pregnant rats and either vehicle or the PPAR-γ antagonist, T0070907 (1mg/kg/day), administered between GD11-15. In a separate study, either vehicle or the PPAR-γ agonist, rosiglitazone (5mg/kg/day), was administered (GD16-18) to normal pregnant or RUPP (produced via surgical reduction of uteroplacental perfusion on GD14) rats in either the absence or presence of the heme oxyenase 1 (HO-1) inhibitor, SnPP (50μmol/kg/day), via drinking water. Animals were chronically catheterized on GD18 for mean arterial blood pressure (MABP) measurement on GD19. In all groups, vascular function was assessed in response to the vasoconstrictor, U46619 (10–9–4×10–7M), and the vasodilators bradykinin (BK; 10–9–10–5M) and sodium nitroprusside (SNP; 10–9–10–5M). Results: Rats which received T0070907 had significantly elevated MABP (p<0.05) and impaired vasorelaxation in response to BK (p<0.05) compared with controls. T0070907 treated rats had reduced pup number and weight and significantly increased placental weight (p<0.05) compared with controls. RUPP rats were characterized by severe hypertension (P<0.001) and impaired vasorelaxation in response to BK (P<0.001). Treatment with rosiglitazone reversed RUPP induced hypertension (P<0.001) and endothelial dysfunction (P<0.05). These effects were abrogated by co-administration of SnPP with rosiglitazone (P<0.01). Conclusions: PPAR-γ antagonism results in a ‘pre-eclamptic’ type model characterised by hypertension, endothelial dysfunction and restricted fetal growth. PPAR-γ activation in the RUPP rat reverses hypertension and endothelial dysfunction through a HO-1 dependent pathway. PPAR-γ agonists may provide a potential therapeutic intervention in the treatment of PE
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