Inhibition of PPARγ during rat pregnancy causes intrauterine growth restriction and attenuation of uterine vasodilation.

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.

Effect of pregnancy and nitric oxide on the myogenic vasodilation of posterior cerebral arteries and the lower limit of cerebral blood flow autoregulation.

Hemorrhage during parturition can lower blood pressure beyond the lower limit of cerebral blood flow (CBF) autoregulation that can cause ischemic brain injury. However, the impact of pregnancy on the lower limit of CBF autoregulation is unknown. We measured myogenic vasodilation, a major contributor of CBF autoregulation, in isolated posterior cerebral arteries (PCAs) from nonpregnant and late-pregnant rats (n = 10/group) while the effect of pregnancy on the lower limit of CBF autoregulation was studied in the posterior cerebral cortex during controlled hemorrhage (n = 8). Pregnancy enhanced myogenic vasodilation in PCA and shifted the lower limit of CBF autoregulation to lower pressures. Inhibition of nitric oxide synthase (NOS) prevented the enhanced myogenic vasodilation during pregnancy but did not affect the lower limit of CBF autoregulation. The shift in the autoregulatory curve to lower pressures during pregnancy is likely protective of ischemic injury during hemorrhage and appears to be independent of NOS.

Pregnant serum induces neuroinflammation and seizure activity via TNFα.

Preeclampsia is a hypertensive disorder of pregnancy that affects many organs including the brain. Neurological complications occur during preeclampsia, the most serious of which is seizure known as eclampsia. Although preeclampsia can precede the eclamptic seizure, it often occurs during normal pregnancy, suggesting that processes associated with normal pregnancy can promote neuronal excitability. Here we investigated whether circulating inflammatory mediators that are elevated late in gestation when seizure also occurs are hyperexcitable to neuronal tissue. Evoked field potentials were measured in hippocampal slices in which control horse serum that slices are normally grown in, was replaced with serum from nonpregnant or late-pregnant Wistar rats for 48 h. We found that serum from pregnant, but not nonpregnant rats, caused hyperexcitability to hippocampal neurons and seizure activity that was abrogated by inhibition of tumor necrosis factor alpha (TNFα) signaling. Additionally, application of TNFα mimicked this increased excitability. Pregnant serum also caused morphological changes in microglia characteristic of activation, and increased TNFα mRNA expression that was not seen with exposure to nonpregnant serum. However, TNFα protein was not found to be elevated in pregnant serum itself, suggesting that other circulating factors during pregnancy caused activation of hippocampal slice cells to produce a TNFα-mediated increase in neuronal excitability. Lastly, although pregnant serum caused neuroinflammation and hyperexcitability of hippocampal slices, it did not increase blood-brain barrier permeability, nor were pregnant rats from which the serum was taken undergoing seizure. Thus, the BBB has an important role in protecting the brain from circulating neuroinflammatory mediators that are hyperexcitable to the brain during pregnancy. These studies provide novel insight into the underlying cause of eclampsia without elevated blood pressure and the protective role of the BBB that prevents exposure of the brain to hyperexcitable factors.

Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling.

Circulating factors in preeclamptic women are thought to cause endothelial dysfunction and thereby contribute to the progression of this hypertensive condition. Despite the involvement of neurological complications in preeclampsia, there is a paucity of data regarding the effect of circulating factors on cerebrovascular function. Using a rat model of pregnancy, we investigated blood-brain barrier permeability, myogenic activity, and the influence of endothelial vasodilator mechanisms in cerebral vessels exposed intraluminally to plasma from normal pregnant or preeclamptic women. In addition, the role of vascular endothelial growth factor signaling in mediating changes in permeability in response to plasma was investigated. A 3-hour exposure to 20% normal pregnant or preeclamptic plasma increased blood-brain barrier permeability by ≈6.5- and 18.0-fold, respectively, compared with no plasma exposure (P<0.01). Inhibition of vascular endothelial growth factor receptor kinase activity prevented the increase in permeability in response to preeclamptic plasma but had no effect on changes in permeability of vessels exposed to normal pregnant plasma. Circulating factors in preeclamptic plasma did not affect myogenic activity or the influence of endothelium on vascular tone. These findings demonstrate that acute exposure to preeclamptic plasma has little effect on reactivity of cerebral arteries but significantly increases blood-brain barrier permeability. Prevention of increased permeability by inhibition of vascular endothelial growth factor signaling suggests that activation of this pathway may be responsible for increased blood-brain barrier permeability after exposure to preeclamptic plasma.

Effect of PPARγ inhibition during pregnancy on posterior cerebral artery function and structure.

Peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor, has protective roles in the cerebral circulation and is highly activated during pregnancy. Thus, we hypothesized that PPARγ is involved in the adaptation of cerebral vasculature to pregnancy. Non-pregnant (NP) and late-pregnant (LP) rats were treated with a specific PPARγ inhibitor GW9662 (10 ]mg/kg/day, in food) or vehicle for 10 days and vascular function and structural remodeling were determined in isolated and pressurized posterior cerebral arteries (PCA). Expression of PPARγ and angiotensin type 1 receptor (AT1R) in cerebral (pial) vessels was determined by real-time RT-PCR. PPARγ inhibition decreased blood pressure and increased blood glucose in NP rats, but not in LP rats. PPARγ inhibition reduced dilation to acetylcholine and sodium nitroprusside in PCA from NP (p < 0.05 vs. LP-GW), but not LP rats. PPARγ inhibition tended to increase basal tone and myogenic activity in PCA from NP rats, but not LP rats. Structurally, PPARγ inhibition increased wall thickness in PCA from both NP and LP rats (p < 0.05), but increased distensibility only in PCA from NP rats. Pregnancy decreased expression of PPARγ and AT1R (p < 0.05) in cerebral arteries that was not affected by GW9662 treatment. These results suggest that PPARγ inhibition had significant effects on the function and structure of PCA in the NP state, but appeared to have less influence during pregnancy. Down-regulation of PPARγ and AT1R in cerebral arteries may be responsible for the lack of effect of PPARγ in cerebral vasculature and may be part of the vascular adaptation to pregnancy.

PPAR-gamma agonist rosiglitazone reverses increased cerebral venous hydraulic conductivity during hypertension.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been shown to protect the cerebral vasculature, including the blood-brain barrier. In the present study, we investigated the effect of the PPAR-gamma agonist rosiglitazone on changes in venous permeability during chronic hypertension induced by nitric oxide synthase inhibition. Female Sprague-Dawley rats were either treated with N(G)-nitro-L-arginine methyl ester (L-NAME; 0.5 g/l in drinking water) for 5 wk (HTN; n = 8), L-NAME for 5 wk plus the PPAR-gamma agonist rosiglitazone (20 mg/kg in food) for the last 3 wk (HTN + Rosi; n = 5), L-NAME for 5 wk plus the superoxide dismutase mimetic Tempol (1 mmol/l in drinking water) for the last 3 wk (HTN + Tempol; n = 8), or were untreated controls (n = 9). Fluid filtration (J(v)/S) and hydraulic conductivity (L(p)) of cerebral veins were compared in vitro between groups after a step increase in pressure from 10 to 25 mmHg to mimic the change in hydrostatic pressure during acute hypertension. Hypertension increased J(v)/S by 2.2-fold and L(p) by 3.2-fold. Rosiglitazone treatment after 2 wk of hypertension completely reversed the increased J(v)/S and L(p) that occurred during hypertension, whereas Tempol had no effect. These results demonstrate that rosiglitazone was effective at reversing changes in venous permeability that occurred during chronic hypertension, an effect that does not appear to be related to its antioxidant properties. Our findings suggest that PPAR-gamma may be a key regulator of blood-brain barrier permeability and a potential therapeutic target during hypertension.