An attempt to promote neo-vascularization by employing a newly synthesized inhibitor of protein tyrosine phosphatase

• Published in: FEBS letters 2002-07, Vol.524 (1), p.54-58
• Main Authors: Soeda, Shinji, Shimada, Takuji, Koyanagi, Satoru, Yokomatsu, Tsutomu, Murano, Tetsuo, Shibuya, Shiroshi, Shimeno, Hiroshi
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Cell Division - drug effects; Cell Movement - drug effects; Cells, Cultured; DFPMPA, α,α-difluoro(phenyl)methylphosphonic acid derivative; DMEM, Dulbecco's modified Eagle's medium; Endothelial Growth Factors - physiology; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; FBS, fetal bovine serum; Human umbilical vein endothelial cell; Humans; HUVEC, human umbilical vein endothelial cells; Lymphokines - physiology; Mice; Mice, Inbred ICR; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Organophosphonates - chemical synthesis; Organophosphonates - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PI-3K, phosphatidylinositol 3′-kinase; Protein tyrosine phosphatase inhibitor; Protein Tyrosine Phosphatases - antagonists & inhibitors; PTP, protein tyrosine phosphatase; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; VEGF, vascular endothelial growth factor; VEGFR-2, VEGF receptor-2 (KDR)
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(02)03002-8

Vascular endothelial growth factor (VEGF) and its receptors play a key role in angiogenesis. VEGF receptor-2 (VEGFR-2) has a tyrosine kinase domain, and, once activated, induces the phosphorylation of cytoplasmic signaling proteins. The phosphorylated VEGFR-2 may be a substrate for intracellular protein tyrosine phosphatases (PTPs) which prevent VEGF signaling. We synthesized a series of α,α-difluoro(phenyl)methylphosphonic acids (DFPMPAs) which inhibit the action of PTP. In this study, we test their effects on VEGF-induced angiogenesis. DFPMPA-3, the most effective inhibitor of human PTP-1B, promoted tube formation by human umbilical vein endothelial cells (HUVEC) on Matrigel more effectively than any other DFPMPAs. The inhibitor promoted the VEGF-induced proliferation and migration of HUVEC by inhibiting the dephosphorylation of VEGFR-2. Its effectiveness was proven through neo-vascularization in mice. The present findings suggest that targeting PTP to promote therapeutic neo-vascularization may be a potential strategy.