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PMID:23139789

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Citation

Bruns, AF, Yuldasheva, N, Latham, AM, Bao, L, Pellet-Many, C, Frankel, P, Stephen, SL, Howell, GJ, Wheatcroft, SB, Kearney, MT, Zachary, IC and Ponnambalam, S (2012) A Heat-Shock Protein Axis Regulates VEGFR2 Proteolysis, Blood Vessel Development and Repair. PLoS ONE 7:e48539

Abstract

Vascular endothelial growth factor A (VEGF-A) binds to the VEGFR2 receptor tyrosine kinase, regulating endothelial function, vascular physiology and angiogenesis. However, the mechanism underlying VEGFR2 turnover and degradation in this response is unclear. Here, we tested a role for heat-shock proteins in regulating the presentation of VEGFR2 to a degradative pathway. Pharmacological inhibition of HSP90 stimulated VEGFR2 degradation in primary endothelial cells and blocked VEGF-A-stimulated intracellular signaling via VEGFR2. HSP90 inhibition stimulated the formation of a VEGFR2-HSP70 complex. Clathrin-mediated VEGFR2 endocytosis is required for this HSP-linked degradative pathway for targeting VEGFR2 to the endosome-lysosome system. HSP90 perturbation selectively inhibited VEGF-A-stimulated human endothelial cell migration in vitro. A mouse femoral artery model showed that HSP90 inhibition also blocked blood vessel repair in vivo consistent with decreased endothelial regeneration. Depletion of either HSP70 or HSP90 caused defects in blood vessel formation in a transgenic zebrafish model. We conclude that perturbation of the HSP70-HSP90 heat-shock protein axis stimulates degradation of endothelial VEGFR2 and modulates VEGF-A-stimulated intracellular signaling, endothelial cell migration, blood vessel development and repair.

Links

PubMed Online version:10.1371/journal.pone.0048539

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A8WFS0

involved_in

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-121213-3

P

Seeded From UniProt

complete

DANRE:B0S610

involved_in

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-121213-3

P

Seeded From UniProt

complete

DANRE:B7ZV46

involved_in

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-121213-3

P

Seeded From UniProt

complete

DANRE:HS90B

involved_in

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-121213-4

P

Seeded From UniProt

complete

DANRE:Q8UUJ8

involved_in

GO:0001568: blood vessel development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-121213-3

P

Seeded From UniProt

complete

HUMAN:VGFR2

GO:0004716: receptor signaling protein tyrosine kinase activity

ECO:0000314:

F

Figure one shows that 'HUVECs were subjected to geldanamycin (17-DMAG) treatment for indicated times, lysed and processed for immunoblotting (IB) to analyze indicated protein levels. Arrowhead indicates mature VEGFR2; TfR, transferrin receptor. (B) Quantification of mature VEGFR2 levels in control and geldanamycin-treated endothelial cells'

complete
CACAO 5697


See also

References

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