Abstract
Decreased peroxisome proliferator-activated receptor gamma (PPARγ) activity is thought to have a major role in preeclampsia through abnormal placental development. However, the role of PPARγ in adaptation of the uteroplacental vasculature that may lead to placental hypoperfusion and fetal growth restriction during pregnancy is not known. Here, pregnant Sprague–Dawley rats (n = 11/group) were treated during the second half of pregnancy with the PPARγ inhibitor GW9662 (10 mg/kg/day in food) or vehicle. Pregnancy outcome and PPARγ mRNA, vasodilation and structural remodeling were determined in maternal uterine and mesenteric arteries. PPARγ was expressed in uterine vascular tissue of both non-pregnant and pregnant rats with ~2-fold greater expression in radial vs. main uterine arteries. PPARγ mRNA levels were significantly higher in uterine compared to mesenteric arteries. GW9662 treatment during pregnancy did not affect maternal physiology (body weight, glucose, blood pressure), mesenteric artery vasodilation or structural remodeling of uterine and mesenteric vessels. Inhibition of PPARγ for the last 10 days of gestation caused decreased fetal weights on both day 20 and 21 of gestation that was associated with impaired vasodilation of radial uterine arteries in response to acetylcholine and sodium nitroprusside. These results define an essential role of PPARγ in the control of uteroplacental vasodilatory function during pregnancy, an important determinant of blood flow to the placenta and fetus. Strategies that target PPARγ activation in the uterine circulation could have important therapeutic potential in treatment of pregnancies complicated by hypertension, diabetes or preeclampsia.
Highlights
Preeclampsia, a life-threatening complication of human pregnancy characterized by proteinuria and the new-onset of hypertension after 20 weeks of gestation, is a major cause of maternal and fetal morbidity and mortality worldwide (Roberts, 1998; Alexander et al, 2001; Sibai et al, 2005)
If PPARγ is expressed in uterine vasculature and if PPARγ expression is modulated during pregnancy has not been shown
This study investigated the role of PPARγ in uteroplacental vascular adaptation to pregnancy and fetal growth by inhibiting PPARγ during the second half of rat pregnancy and assessing fetal outcome, uterine vascular remodeling and vasodilatory function
Summary
Preeclampsia, a life-threatening complication of human pregnancy characterized by proteinuria and the new-onset of hypertension after 20 weeks of gestation, is a major cause of maternal and fetal morbidity and mortality worldwide (Roberts, 1998; Alexander et al, 2001; Sibai et al, 2005). The uterine circulation undergoes considerable structural and functional changes to facilitate a large increase in uterine blood flow necessary for successful pregnancy (Sibai et al, 2005; Osol and Mandala, 2009) During preeclampsia, this circulation is significantly affected due to decreased vasodilator production and outward remodeling of uterine spiral vessels (Roberts, 1998; Sibai et al, 2005; Gilbert et al, 2008; Burton et al, 2009). Recent studies have demonstrated that PPARγ expression has an essential role in trophoblast differentiation, invasion www.frontiersin.org
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