PPARγ Links BMP2 and TGFβ1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism

Cell Metab. 2017 May 2;25(5):1118-1134.e7. doi: 10.1016/j.cmet.2017.03.011.


BMP2 and TGFβ1 are functional antagonists of pathological remodeling in the arteries, heart, and lung; however, the mechanisms in VSMCs, and their disturbance in pulmonary arterial hypertension (PAH), are unclear. We found a pro-proliferative TGFβ1-Stat3-FoxO1 axis in VSMCs, and PPARγ as inhibitory regulator of TGFβ1-Stat3-FoxO1 and TGFβ1-Smad3/4, by physically interacting with Stat3 and Smad3. TGFβ1 induces fibrosis-related genes and miR-130a/301b, suppressing PPARγ. Conversely, PPARγ inhibits TGFβ1-induced mitochondrial activation and VSMC proliferation, and regulates two glucose metabolism-related enzymes, platelet isoform of phosphofructokinase (PFKP, a PPARγ target, via miR-331-5p) and protein phosphatase 1 regulatory subunit 3G (PPP1R3G, a Smad3 target). PPARγ knockdown/deletion in VSMCs activates TGFβ1 signaling. The PPARγ agonist pioglitazone reverses PAH and inhibits the TGFβ1-Stat3-FoxO1 axis in TGFβ1-overexpressing mice. We identified PPARγ as a missing link between BMP2 and TGFβ1 pathways in VSMCs. PPARγ activation can be beneficial in TGFβ1-associated diseases, such as PAH, parenchymal lung diseases, and Marfan's syndrome.

Keywords: FoxO1; PFKP; PPP1R3G; Smad3; Stat3; miR-130a/301b; miR331-5p; platelet isoform of phosphofructokinase; protein phosphatase 1 regulatory subunit 3G; pulmonary arterial hypertension.

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 2 / metabolism*
  • Cell Proliferation*
  • Cells, Cultured
  • Female
  • Glucose / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / metabolism
  • PPAR gamma / metabolism*
  • Pulmonary Artery / cytology
  • Pulmonary Artery / metabolism
  • Signal Transduction*
  • Transforming Growth Factor beta1 / metabolism*


  • Bone Morphogenetic Protein 2
  • PPAR gamma
  • Transforming Growth Factor beta1
  • Glucose