+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Journal of Experimental Medicine 211(6): 1167-1183

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 053692298

Download citation: RISBibTeXText

PMID: 24863063

DOI: 10.1084/jem.20132330

Related references

Targeting of integrin-linked kinase with small interfering RNA inhibits VEGF-induced angiogenesis in retinal endothelial cells. Ophthalmic Research 49(3): 139-149, 2013

Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutrition and Cancer 61(4): 554-563, 2009

Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 99(1): 383-388, 2002

A novel peptide from human apolipoprotein(a) inhibits angiogenesis and tumor growth by targeting c-Src phosphorylation in VEGF-induced human umbilical endothelial cells. International Journal of Cancer 124(4): 843-852, 2009

miR-101 inhibits cholangiocarcinoma angiogenesis through targeting vascular endothelial growth factor (VEGF). American Journal of Pathology 182(5): 1629-1639, 2014

Oligo-guanosine nucleotide induces neuropilin-1 internalization in endothelial cells and inhibits angiogenesis. Blood 116(16): 3099-3107, 2010

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. International Journal of Oncology 52(4): 1350-1362, 2018

Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. Plos One 7(3): E33418-E33418, 2012

BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance. Journal of Hematology & Oncology 4(): 6-6, 2011

Kaempferol inhibits angiogenic ability by targeting VEGF receptor-2 and downregulating the PI3K/AKT, MEK and ERK pathways in VEGF-stimulated human umbilical vein endothelial cells. Oncology Reports: -, 2018

A placental growth factor variant unable to recognize vascular endothelial growth factor (VEGF) receptor-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization. Cancer Research 70(5): 1804-1813, 2010

Vascular endothelial growth factor-b (VEGF-B) induces myocardium-specific angiogenesis via VEGFR-1 and neuropilin-1. Circulation 116(16): 49, 2007

Comparative biological effects of VEGF and VEGF-C on endothelial cells Role of neuropilin-1 and Flk-1/KDR receptors. FASEB Journal 15(5): A1078, March 8, 2001

Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells: IMPLICATIONS IN VEGF-DEPENDENT ANGIOGENESIS AND DIABETIC WOUND HEALING. Journal of Biological Chemistry 292(2): 407-416, 2016

Neuropilin-1 is required for vascular development and is a mediator of VEGF-dependent angiogenesis in zebrafish. Proceedings of the National Academy of Sciences of the United States of America 99(16): 10470-5, 2002