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Updated: May 7, 2026
Isolation and Cannulation of Cerebral Parenchymal Arterioles
Published on: May 23, 2016
PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain
A Duelsner1, N Gatzke, P Hillmeister
1Center for Cardiovascular Research (CCR), Richard-Thoma-Laboratories for Arteriogenesis, Charité - Universitaetsmedizin Berlin, Berlin, Germany.
Insights
PPARγ stimulation, while improving cardiovascular risk factors, hinders adaptive and therapeutic cerebral collateral growth by interfering with key cellular processes. This suggests a potential mechanism for cardiovascular risks associated with thiazolidinedione use.
Area of Science:
- Vascular Biology
- Pharmacology
- Cardiovascular Research
Background:
- Peroxisome proliferator-activated receptor gamma (PPARγ) agonists improve cardiovascular (CV) risk factors but not overall clinical outcomes.
- PPARγ agonists impact endothelial cells (EC), monocytes, and smooth muscle cells (SMC), which are crucial for arterial collateral growth (arteriogenesis).
Purpose of the Study:
- To investigate the effect of PPARγ stimulation on adaptive and therapeutic cerebral collateral growth.
- To determine if PPARγ stimulation influences the cellular mechanisms involved in arteriogenesis.
Main Methods:
- A rat model of adaptive cerebral arteriogenesis (3-VO) was used.
- Animals were treated with pioglitazone (a PPARγ agonist) alone or in combination with G-CSF.
- Effects on collateral growth, hemodynamic reserve capacity, and cellular functions (EC, SMC, monocyte) were assessed.
Main Results:
- PPARγ stimulation significantly decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity.
- Pioglitazone counteracted G-CSF-induced therapeutic arteriogenesis.
- PPARγ stimulation interfered with EC activation, SMC proliferation, and monocyte activation/migration.
Conclusions:
- Pharmacologic PPARγ stimulation inhibits pro-arteriogenic cellular processes, impairing both adaptive and therapeutic cerebral arteriogenesis.
- These findings suggest a potential mechanism linking thiazolidinedione use to adverse CV risks.
- Further research is warranted to explore this connection in patients.
Aims:
PPARγ stimulation improves cardiovascular (CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell (EC), monocyte and smooth muscle cell (SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth.
Methods:
In a rat model of adaptive cerebral arteriogenesis (3-VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg(-1); 10 mg kg(-1) compared with metformin 62.2 mg kg(-1) or sitagliptin 6.34 mg kg(-1)) for 21 days or (iii) after adding pioglitazone to G-CSF (40 μg kg(-1) every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied.
Results:
PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity (CVRC controls: 12 ± 7%; pio low: -2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G-CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration.
Conclusion:
Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G-CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients.
