Pleiotrophin, a multifunctional angiogenic factor: Mechanisms and pathways in normal and pathological angiogenesis

PURPOSE OF REVIEW: This study seeks to integrate recent studies that identify new critical mechanisms through which the 136 amino acid secreted heparin-binding cytokine pleiotrophin (PTN, Ptn) stimulates both normal and pathological angiogenesis. RECENT FINDINGS: Pleiotrophin is directly angiogenic; it initiates an angiogenic switch in different cancer models in vivo. It acts as an angiogenic factor through multiple mechanisms that include a unique signaling pathway that activates newly identified downstream tyrosine kinases through a unique mechanism, an interaction with endothelial cells to initiate proliferation, migration, and tube formation, the regulation of basic fibroblast growth factor and vascular endothelial growth factor signaling, the remodeling of the stromal microenvironment, and induction of transdifferentiation of monocytes into endothelial cells. Recently also, domains of PTN that stimulate angiogenesis and peptides that function to inhibit PTN signaling have been identified. SUMMARY: Recent studies have identified new mechanisms dependent on activation of the PTN signaling pathway that regulate angiogenesis and new targets to use PTN to both stimulate angiogenesis and block its activity to control pathological angiogenesis.