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

placental protein 13 pp13 induced vasodilation of resistance arteries from pregnant and nonpregnant rats occurs via endothelial signaling pathways

ABSTRACTPlacental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects on isolated uterine arteries from nonpregnant and mid-pregnant rats. Vessels were isolated, cannulated, and pressurized to 50 mmHg within an arteriograph, preconstricted and exposed to increasing PP13 concentrations (10−13–10−8 M). PP13 elicited 38–50% arterial vasodilation with half-maximum response (EC50) = 1 pM. The relaxation was mediated by activating the endothelial-signaling pathways of prostaglandin and nitric oxide (NO). Accordingly, these results encourage evaluation of PP13 as a possible therapy for gestational diseases characterized by insufficient uteroplacental blood flow and/or maternal hypertension

Mechanisms of enhanced basal tone of brain parenchymal arterioles during early postischemic reperfusion: Role of ET-1-induced peroxynitrite generation

The contributions of vasoconstrictors (endothelin-1 (ET-1), peroxynitrite) and endothelium-dependent vasodilatory mechanisms to basal tone were investigated in parenchymal arterioles (PAs) after early postischemic reperfusion. Transient middle cerebral artery occlusion (tMCAO) was induced for 2 hours with 30 minutes reperfusion in male Wistar rats and compared with ischemia alone (permanent MCAO (pMCAO); 2.5 hours) or sham controls. Changes in lumen diameter of isolated and pressurized PAs were compared. Quantitative PCR was used to measure endothelin type B (ET(B)) receptors. Constriction to intravascular pressure (‘basal tone') was not affected by tMCAO or pMCAO. However, constriction to inhibitors of endothelial cell, small- (SK) and intermediate- (IK) conductance, Ca(2+)-sensitive K(+) channels (apamin and TRAM-34, respectively) were significantly enhanced in PAs from tMCAO compared with pMCAO or sham. Addition of the ET(B) agonist sarafotoxin caused constriction in PAs from tMCAO but not from sham animals (21±4% versus 3±3% at 1 nmol/L; P<0.01) that was inhibited by the peroxynitrite scavenger FeTMPyP (5,10,15,20-tetrakis (N-methyl-4′-pyridyl) porphinato iron (III) chloride) (100 μmol/L). Expression of ET(B) receptors was not found on PA smooth muscle, suggesting that constriction to sarafotoxin after tMCAO was due to peroxynitrite and not ET(B) receptor expression. The maintenance of basal tone in PAs after tMCAO may restrict flow to the ischemic region and contribute to infarct expansion