Abstract
Background and AimInsufficient post-ischemic neovascularization is an initial key step in the pathogenesis of Oxygen-Induced Retinopathy (OIR). During neovascularization, pro-angiogenic cells (PACs) are mobilized from the bone marrow and integrate into ischemic tissues to promote angiogenesis. However, the modulation of PAC paracrine activity during OIR and the specific mechanisms involved remain to be explored. Because Tyrosine-protein phosphatase non-receptor type 9 (PTPN9) is reported to be a negative regulator of stem cell differentiation and angiogenesis signaling, we investigated its effect on PAC activity in the context of OIR.Methods and ResultsIn a rat model of OIR, higher levels of PTPN9 in the retina and in bone marrow derived PACs are associated with retinal avascular areas, lower levels of the mobilization factor SDF-1 and decreased number of CD34+/CD117+/CD133+ PACs. PACs exposed ex vivo to hyperoxia display increased PTPN9 expression, which is associated with impaired ability of PAC secretome to promote angiogenesis ex vivo (choroidal vascular sprouting) and in vitro (endothelial cell tubule formation) compared to the secretome of PACs maintained in normoxia. Suppression of PTPN9 (using siRNA) increases VEGF and SDF-1 expression to normalize PAC secretome during hyperoxia, leading to restored angiogenic ability of PAC secretome. Moreover, endothelial cells exposed to the secretome of siPTPN9-treated PACs expressed increased levels of activated form of VEGF receptor 2 (VEGFR2). In the rat model of OIR, intravitreal injection of secretome from siPTPN9-treated PACs significantly reduced retinal vaso-obliteration; this was associated with higher retinal levels of VEGF/SDF-1, and increased recruitment of PACs (CD34+ cells) to the retinal and choroidal vessels.ConclusionOur results suggest that hyperoxia alters the paracrine proangiogenic activity of BM-PACs by inducing PTPN9, which can contribute to impair post-ischemic revascularization in the context of OIR. Targeting PTPN9 restores PAC angiogenic properties, and provide a new target for vessel integrity in ischemic retinopathies.
Highlights
Retinopathy of prematurity (ROP) remains a leading cause of visual impairment and blindness in premature neonates worldwide (Rivera et al, 2016)
We evaluated the efficacy of proangiogenic cells (PACs) secretome to promote HMREC tubulogenesis and angiogenic sprouting of rat choroidal explant compared to endothelial growth medium [EGM; used as positive control (CTL)], and in this process evaluated effects of ex vivo hyperoxia (80% O2 for 24 h) on PAC paracrine activities; supernatant was collected at 24 h
Based on the importance of protein phosphatase non-receptor type 9 (PTPN9) in stem cell mobilization and maintenance and angiogenic function (Corti and Simons, 2017; Hale et al, 2017), we investigated the role of PTPN9 on paracrine angiogenic activities of PACs as summarize in Supplementary Figure 2A
Summary
Retinopathy of prematurity (ROP) remains a leading cause of visual impairment and blindness in premature neonates worldwide (Rivera et al, 2016) This multifactorial ocular disease is characterized by an initial phase of retinal vascular degeneration resulting in retinal ischemia, which in turn predisposes to excessive pathological intravitreal neovascularization. Whereas relatively little is known to either maintain vessel integrity or promote revascularization during the initial phase of ischemia; this knowhow could yield approaches to limit subsequent pathological neovascularization In this regard, angiogenic therapies using stem cell supplementation have recently been shown to promote vascular repair in ischemic animal models (Leeper et al, 2010; Bian et al, 2019). Because Tyrosine-protein phosphatase non-receptor type 9 (PTPN9) is reported to be a negative regulator of stem cell differentiation and angiogenesis signaling, we investigated its effect on PAC activity in the context of OIR
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