RGD Reference Report - Proangiogenic effects of protease-activated receptor 2 are tumor necrosis factor-alpha and consecutively Tie2 dependent. - Rat Genome Database

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Proangiogenic effects of protease-activated receptor 2 are tumor necrosis factor-alpha and consecutively Tie2 dependent.

Authors: Zhu, T  Sennlaub, F  Beauchamp, MH  Fan, L  Joyal, JS  Checchin, D  Nim, S  Lachapelle, P  Sirinyan, M  Hou, X  Bossolasco, M  Rivard, GE  Heveker, N  Chemtob, S 
Citation: Zhu T, etal., Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):744-50. Epub 2006 Jan 26.
RGD ID: 2314218
Pubmed: PMID:16439712   (View Abstract at PubMed)
DOI: DOI:10.1161/01.ATV.0000205591.88522.d4   (Journal Full-text)

OBJECTIVE: Angiogenesis is essential physiologically in growth and pathologically in tumor development, chronic inflammatory disorders, and proliferative retinopathies. Activation of protease-activated receptor 2 (PAR2) leads to a proangiogenic response, but its mechanisms have yet to be specifically described. Here, we investigated the mode of action of PAR2 in retinal angiogenesis. METHODS AND RESULTS: PAR2-activating peptide, SLIGRL, increased retinal angiogenesis associated with an induction of vascular endothelial growth factor and angiopoetin-2 and most notably tie2 in the retina in vivo as well as in cultured neuroretinal endothelial cells. SLIGRL also induced release of the proinflammatory and angiogenic mediator tumor necrosis factor-alpha (TNF-alpha) via the MEK/extracellular signal-regulated kinase (ERK) (MEK/ERK) pathway in these endothelial cells. TNF-alpha, in turn, elicited tie2 expression by activating the MEK/ERK pathway. PAR2-evoked tie2 expression, endothelium proliferation (in vitro), and retinal neovascularization (in vivo) were abrogated by selective TNF-alpha blockers (neutralizing antibody infliximab and soluble TNF-alpha receptor-Fc fusion protein etanercept) as well as the MEK inhibitor PD98059. CONCLUSIONS: The proangiogenic properties of PAR2 are intertwined with its proinflammatory effects, such that in retinal vasculature, they depend on TNF-alpha and subsequent induction of tie2 via the MEK/ERK pathway.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
angiogenesis  IEP 2314218 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Angpt2  (angiopoietin 2)


Additional Information