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


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.
Zhu
Tang
T
Department of Pediatrics, Research Center of Hôpital Ste-Justine, Montréal, Quebec, Canada.
Sennlaub
Florian
F
Beauchamp
Martin Hervé
MH
Fan
Li
L
Joyal
Jean Sebastian
JS
Checchin
Daniella
D
Nim
Satra
S
Lachapelle
Pierre
P
Sirinyan
Mirna
M
Hou
Xin
X
Bossolasco
Michela
M
Rivard
Georges-Etienne
GE
Heveker
Nikolaus
N
Chemtob
Sylvain
S
D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology; D018919:Neovascularization, Physiologic; D009842:Oligopeptides / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000378:metabolism; D012160:Retina / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042702:Angiopoietin-2; D009842:Oligopeptides; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D042787:Receptor, TIE-2