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

Abstract

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.

Keywords: peroxisome proliferator-activated receptor-γ; posterior cerebral arteries; pregnancy; vascular remodeling; vasodilation.

Figure 1

Graph showing percent tone of PCA at intraluminal pressure of 75 mmHg from non-pregnant (NP), NP treated with the PPARγ inhibitor GW9622 (NP + GW), late-pregnant (LP), LP treated with GW9662 (LP + GW). PPARγ inhibition tended to increase tone in NP-GW rats (p = 0.08), but had no effect on pregnant rats.

Figure 2

Graph showing active internal diameters versus intraluminal pressure of PCA in (A) non-pregnant (NP) and GW9662-treated NP (NP + GW) groups; (B) late-pregnant (LP) and GW9662-treated LP (LP + GW) groups. Myogenic activity in PCA was demonstrated by constriction in response to increases in pressure and tended to be increased in NP-GW but not in PCA from LP or LP-GW rats.

Figure 3

Graph showing percent dilation of PCA in response to (A) ACh (10⁻⁸–10⁻⁵ M) and (B) SNP (10⁻⁸–10⁻⁵ M) from non-pregnant (NP), NP treated with the PPARγ inhibitor GW9622 (NP + GW), late-pregnant (LP), LP treated with GW9662 (LP + GW). Note that two-way ANOVA revealed that dilation to ACh (3 × 10⁻⁷–10⁻⁵ M) and SNP (10⁻⁷–10⁻⁵ M) in PCA from NP + GW rats was significantly different from that of LP + GW rats. *p < 0.05 vs. LP + GW.

Figure 4

Graph showing passive distensibility versus intraluminal pressure of PCA in (A) non-pregnant (NP) and GW9662-treated NP (NP + GW) groups; (B) late-pregnant (LP) and GW9662-treated LP (LP + GW) groups; (C) NP and LP groups; and (D) NP + GW and LP + GW groups. *p < 0.05: NP vs. NP + GW; †p < 0.05: NP vs. LP.

Figure 5

Graph showing relative changes in mRNA expression of (A) PPARγ and (B) angiotensin type 1 receptors (AT1R) in cerebral vessels of non-pregnant (NP), NP + GW9662 (NP + GW), late-pregnant (LP), and LP + GW9662 (LP + GW) groups. Results are presented as percent change in gene expression normalized to β2-microglobulin (B2M), an endogenous reference gene, and relative to the untreated NP group (n = 7–8, mean ± SEM). Expression of PPARγ and AT1R was decreased in cerebral vessels from LP rats but unaffected by GW9662 treatment. *p < 0.05 vs. NP, †p < 0.05 vs. NP + GW.