PPARs and angiogenesis

The PPAR (peroxisome-proliferator-activated receptor) family consists of three ligand-activated nuclear receptors: PPAR alpha, PPAR beta/delta and PPAR gamma. These PPARs have important roles in the regulation of glucose and fatty acid metabolism, cell differentiation and immune function, but were also found to be expressed in endothelial cells in the late 1990s. The early endothelial focus of PPARs was PPAR gamma, the molecular target for the insulin-sensitizing thiazolidinedione/glitazone class of drugs. Activation of PPAR gamma was shown to inhibit angiogenesis in vitro and in models of retinopathy and cancer, whereas more recent data point to a critical role in the development of the vasculature in the placenta. Similarly, PPAR alpha, the molecular target for the fibrate class of drugs, also has anti-angiogenic properties in experimental models. In contrast, unlike PPAR alpha or PPAR gamma, activation of PPAR beta/delta induces angiogenesis, in vitro and in vivo, and has been suggested to be a critical component of the angiogenic switch in pancreatic cancer. Moreover, PPAR beta/delta is an exercise mimetic and appears to contribute to the angiogenic remodelling of cardiac and skeletal muscle induced by exercise. This evidence and the emerging mechanisms by which PPARs act in endothelial cells are discussed in more detail.