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Updated: Aug 13, 2026

Characterizing Modulators of Protease-Activated Receptors with a Calcium Mobilization Assay Using a Plate Reader
Published on: May 24, 2024
Proangiogenic effects of protease-activated receptor 2 are tumor necrosis factor-alpha and consecutively Tie2
Tang Zhu1, Florian Sennlaub, Martin Hervé Beauchamp
1Department of Pediatrics, Research Center of Hôpital Ste-Justine, Montréal, Quebec, Canada.
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.
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