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Nicholas Sitaras, Jose C Rivera, Baraa Noueihed, Przemyslaw Mike Sapieha, Jean-Sebasiten Joyal, Sylvain Chemtob; Neurons enhance revascularization of the ischemic retina by PAR2 via negative regulation of IL-1RI. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1267.
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Proliferative Retinopathies (PRs) are biphasic disorders characterized by an initial phase of vaso-obliteration (VO) followed by ischemia-induced neovascularization (NV) phase, which can result in blinding retinal detachment. Revascularization of ischemic retina presents a therapeutic avenue for treating these diseases. In PRs, inflammation results in secretion of IL-1, which contributes to vascular degeneration and prevents normal revascularization of the ischemic retina. Since proteases are necessary for the formation of the vascular network and that IL-1 induces expression of pro-angiogenic protease-activated receptor 2 (PAR2), we hypothesized that PAR2 may modulate deleterious effects of IL-1.
New-born mice pups were exposed to OIR model (75% O2 from P7-P12). Localization studies was assessed using IHC analysis. Intravitreal injections of lentiviral constructs bearing shRNA versus PAR2 (Lv.shPAR2) was used to conditionally knockdown (KD) PAR2 while PAR2 peptidyl agonist (PAR2-AP), SLIGRL, served as activating peptide. Cultured retinal ganglion cells (RGC) and endothelial cells (EC) were used as ex vivo models.
PAR2 was mostly expressed in RGCs and to a lesser extent in retinal ECs; this expression was increased early during exposure to hyperoxia (from P8-P12). Surprisingly, subjecting PAR2-null mice to OIR did not modify the degree of VO and subsequent NV; we surmised compensatory mechanisms in germ cell line PAR2-null mice. We therefore utilized a conditional knockdown (KD) approach by intravitreal injection of Lv.shPAR2. PAR2 KD diminished normal revascularization resulting in greater intra-vitreal NV; conversely PAR2-AP accelerated normal revascularization. Exploration in vitro in RGC and EC and in vivo of implicated mechanisms, showed that IL-1 was responsible for inducing PAR2 expression, while increased PAR2 activation in turn suppressed IL-1RI through a ERK1/2-dependent process in neurons only. Decreased IL-1RI expression abrogated effects of IL-1-mediated expression of the endothelial pro-apoptotic and vaso-repulsive Semaphorin 3A.
All together, our findings underline an important mechanism by which PAR2 regulates vascular degeneration by repressing IL-1RI and subsequently Sema3A. Timely activation of PAR2 or inhibition of IL-1RI may offer therapeutic avenue in curbing aberrant intravitreal neovascularization as well as preserving retinal integrity.
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