Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation

Abstract

Although peroxisome proliferator-activated receptor-γ (PPARγ) is thought to play a protective role in the vasculature, its cell-specific effect, particularly in resistance vessels, is poorly defined. Nitric oxide (NO) plays a major role in vascular biology in the brain. We examined the hypothesis that selective interference with PPARγ in vascular muscle would impair NO-dependent responses and augment vasoconstrictor responses in the cerebral circulation. We studied mice expressing a dominant negative mutation in human PPARγ (P467L) under the control of the smooth muscle myosin heavy chain promoter (S-P467L). In S-P467L mice, dilator responses to exogenously applied or endogenously produced NO were greatly impaired in cerebral arteries in vitro and in small cerebral arterioles in vivo. Select NO-independent responses, including vasodilation to low concentrations of potassium, were also impaired in S-P467L mice. In contrast, increased expression of wild-type PPARγ in smooth muscle had little effect on vasomotor responses. Mechanisms underlying impairment of both NO-dependent and NO-independent vasodilator responses after interference with PPARγ involved Rho kinase with no apparent contribution by oxidative stress-related mechanisms. These findings support the concept that via effects on Rho kinase-dependent signaling, PPARγ in vascular muscle is a major determinant of vascular tone in resistance vessels and, in particular, NO-mediated signaling in cerebral arteries and brain microvessels. Considering the importance of NO and Rho kinase, these findings have implications for regulation of cerebral blood flow and the pathogenesis of large and small vessel disease in brain.

Keywords: cerebral arteries; microcirculation; nitric oxide; small vessel disease.

Figure 1

Baseline diameter (A) of basilar arteries from non-Tg (n=25), S-P467L (n=21), and S-WT mice (n=6). Dilation of the basilar artery to nitroprusside (B)(n=9–11), acetylcholine (C)(n=21–25), and Ang 1-7 (D)(n=12–19) in non-Tg, S-P467L, and S-WT mice. * P<0.01 vs non-Tg, # P<0.05 vs non-Tg.

Figure 2

Changes in diameter of cerebral arterioles in response to acetylcholine (A) and nitroprusside (B) in non-Tg (n=15) and S-P467L (n=12) mice. *P<0.05 vs non-Tg.

Figure 3

Dilation of the basilar artery to KCl in non-Tg mice in the absence or presence of barium (A)(n=3–6). Effects of Y-27632 on dilation of the basilar artery to KCl (B)(n=6–9) and responses to KCl in S-WT mice (C)(n=6). Responses of the basilar artery to arachidonic acid (D)(n=6), cromakalim (E)(n=5–8), and nifedipine (F)(n=5–10) in non-Tg and S-P467L mice, along with responses to papaverine (F) in non-Tg (n=25), S-P467L (n=21), and S-WT (n=6) mice. * P<0.01 vs non-Tg.

Figure 4

Effects of Y-27632 on dilation of the basilar artery to nitroprusside (A)(n=5) and Ang 1-7 (B)(n=6) in S-P467L mice and effects of Y-27632 on Ang 1-7 responses in non-Tg (n=5). * P<0.01 vs non-Tg.

Figure 5

Responses of the basilar artery to serotonin (A)(n=11–15) and endothelin-1 (B) (n=9) in non-Tg and S-P467L mice in the absence and presence of Y-27632 (n=6–8). Responses to KCl in non-Tg (n=25), S-P467L (n=21), and S-WT (n=6) mice are also shown (C). * P<0.05 vs non-Tg.