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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:744.)
© 2006 American Heart Association, Inc.

Vascular Biology

Proangiogenic Effects of Protease-Activated Receptor 2 Are Tumor Necrosis Factor- and Consecutively Tie2 Dependent

Tang Zhu; Florian Sennlaub; Martin Hervé Beauchamp; Li Fan; Jean Sebastian Joyal; Daniella Checchin; Satra Nim; Pierre Lachapelle; Mirna Sirinyan; Xin Hou; Michela Bossolasco; Georges-Etienne Rivard; Nikolaus Heveker; Sylvain Chemtob

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.

Correspondence to Sylvain Chemtob, MD, PhD, Hôpital Ste-Justine, Research Center, 3175 Côte Ste-Catherine, Montréal, Québec, H3T 1C5, Canada. 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) (MEK/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.

This article investigated PAR2 activation in retinal angiogenesis. TNF- inhibitors (infliximab and etanercept) and the MEK inhibitor PD98059 prevented tie2 upregulation, endothelium proliferation, and retinal neovascularization induced by PAR2 activation. The PAR2 proangiogenic properties are involved in its proinflammatory effects 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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