PPARγ in Angiogenesis and Vascular Development

In recent years several molecular and cellular mechanisms have been elucidated that regulate angiogenesis and vascular development. As a result some therapeutic interventions are now available with the potential to enhance normal vascular development and/or to modulate vascular-based disease. The nuclear hormone receptor PPARγ and its clinically useful pharmacologic ligands also modulate angiogenesis and vascular development by actions on both endothelial cells and other cell types. This involves specific effects on the molecular interaction partners and target genes of PPARγ, compensatory changes in processes primarily regulated by other proteins including other PPAR family members, coactivators and corepressors, and “off target” effects involving other signaling pathways. Despite this progress, several factors interfere with determining the specific functions of PPARγ in blood vessel formation and thus with developing PPARγ-based strategies to modulate angiogenesis and vascular development for therapeutic benefit. This review summarizes current proposals for PPARγ functions in angiogenesis and vascular development and emphasizes the complexity of PPARγ gene expression, molecular isoforms with unique functions and unknown expression patterns, the paucity of physiologically relevant endogenous ligands, uncertainties about the specificity of exogenous ligands, and the complex molecular interactions of PPARγ with coregulators and other modifiers. These features are likely responsible for many of the conflicting results obtained in studies of PPARγ in blood vessels and other tissues. Considering these challenges suggests new experimental approaches and future scientific directions that should support significant benefits in a variety of clinical settings involving angiogenesis and vascular development.