Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells.

Abstract

To enable new blood vessel growth, endothelial cells (ECs) express neuropilin 1 (NRP1), and NRP1 associates with the receptor tyrosine kinase VEGFR2 after binding the vascular endothelial growth factor A (VEGF) to enhance arteriogenesis. We report that NRP1 contributes to angiogenesis through a novel mechanism. In human and mouse ECs, the integrin ligand fibronectin (FN) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin (PXN) in a VEGF/VEGFR2-independent but NRP1-dependent manner. NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling. This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo. Accordingly, both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib, a small molecule inhibitor of ABL1 which is widely used to prevent the proliferation of tumor cells that express BCR-ABL fusion proteins. The finding that NRP1 regulates angiogenesis in a VEGF- and VEGFR2-independent fashion via ABL1 suggests that ABL1 inhibition provides a novel opportunity for anti-angiogenic therapy to complement VEGF or VEGFR2 blockade in eye disease or solid tumor growth.

• Authors: Claudio Raimondi, Alessandro Fantin, Anastasia Lampropoulou, Laura Denti, Anissa Chikh, Christiana Ruhrberg
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 211 Issue 6 Pg. 1167-83 (Jun 02 2014) ISSN: 1540-9538 [Electronic] United States
• PMID: 24863063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Raimondi et al.

Chemical References

• Benzamides
• Fibronectins
• Paxillin
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Vascular Endothelial Growth Factor A
• Neuropilin-1
• Imatinib Mesylate
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-abl

Topics

• Animals
• Benzamides (pharmacology)
• Cell Adhesion (genetics)
• Cell Movement (genetics)
• Cells, Cultured
• Endothelial Cells (drug effects, metabolism, physiology)
• Enzyme Activation (drug effects)
• Fibronectins (metabolism)
• Humans
• Imatinib Mesylate
• Immunoblotting
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microscopy, Confocal
• Neovascularization, Physiologic (drug effects)
• Neuropilin-1 (genetics, metabolism)
• Paxillin (metabolism)
• Phosphorylation (drug effects)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-abl (genetics, metabolism)
• Pyrimidines (pharmacology)
• RNA Interference
• Retinal Neovascularization (genetics, physiopathology, prevention & control)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)