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

BMP2 and TGF beta 1 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 TGF beta 1-Stat3-FoxO1 axis in VSMCs, and PPAR gamma as inhibitory regulator of TGF beta 1-Stat3-FoxO1 and TGF beta 1-Smad3/4, by physically interacting with Stat3 and Smad3. TGF beta 1 induces fibrosis-related genes and miR-130a/301b, suppressing PPAR gamma. Conversely, PPAR gamma inhibits TGF beta 1-induced mitochondrial activation and VSMC proliferation, and regulates two glucose metabolism-related enzymes, platelet isoform of phosphofructokinase (PFKP, a PPAR gamma target, via miR-331-5p) and protein phosphatase 1 regulatory subunit 3G (PPP1R3G, a Smad3 target). PPAR gamma knockdown/deletion in VSMCs activates TGF beta 1 signaling. The PPAR gamma agonist pioglitazone reverses PAH and inhibits the TGF beta 1-Stat3-FoxO1 axis in TGF beta 1-overexpressing mice. We identified PPAR gamma as a missing link between BMP2 and TGF beta 1 pathways in VSMCs. PPAR gamma activation can be beneficial in TGF beta 1-associated diseases, such as PAH, parenchymal lung diseases, and Marfan's syndrome.