on January 26, 2006
Published online before print January 26, 2006, doi: 10.1161/01.ATV.0000205591.88522.d4
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Submitted on October 17, 2005
Accepted on January 4, 2006
Proangiogenic Effects of Protease-Activated Receptor 2 Are Tumor Necrosis Factor-
and Consecutively Tie2 Dependent
Tang Zhu ;
From the Departments of Pediatrics, Ophthalmology, Pharmacology (T.Z., F.S., M.H.B., D.C., S.N., M.S., X.H., M.B., S.C.), Hematology (L.F., G.E.R.), and Biochemistry (N.H.), Research Center of Hôpital Ste-Justine, Montréal, Quebec, Canada; and Departments of Ophthalmology, McGill University (P.L.), Montréal, Quebec, Canada.
* To whom correspondence should be addressed. E-mail: sylvain.chemtob{at}umontreal.ca.
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-
(TNF-) via the MEK/extracellular signal-regulated kinase (ERK) pathway in these endothelial cells. TNF-, 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- blockers (neutralizing antibody infliximab and soluble TNF- receptor-Fc fusion protein etanercept) as well as the MEK inhibitor PD98059.
Conclusion--The proangiogenic properties of PAR2 are intertwined with its proinflammatory effects, such that in retinal vasculature, they depend on TNF- and subsequent induction of tie2 via the MEK/ERK pathway.
Key words: protease-activated receptor 2 • angiogenesis • TNF-
•
tie2 receptor •
signaling transduction
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