Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease

Abstract

Angiogenic factors play an important role in the pathogenesis of diabetic retinopathy (DR), neovascular age-related macular degeneration (nAMD) and retinopathy of prematurity (ROP). Pleiotrophin, a well-known angiogenic factor, was recently reported to be upregulated in the vitreous fluid of patients with proliferative DR (PDR). However, its pathogenic role and therapeutic potential in ocular vascular diseases have not been defined in vivo. Here using corneal pocket assays, we demonstrated that pleiotrophin induced angiogenesis in vivo. To investigate the pathological role of pleiotrophin we used neutralizing antibody to block its function in multiple in vivo models of ocular vascular diseases. In a mouse model of DR, intravitreal injection of pleiotrophin-neutralizing antibody alleviated diabetic retinal vascular leakage. In a mouse model of oxygen-induced retinopathy (OIR), which is a surrogate model of ROP and PDR, we demonstrated that intravitreal injection of anti-pleiotrophin antibody prevented OIR-induced pathological retinal neovascularization and aberrant vessel tufts. Finally, pleiotrophin-neutralizing antibody ameliorated laser-induced choroidal neovascularization, a mouse model of nAMD, suggesting that pleiotrophin is involved in choroidal vascular disease. These findings suggest that pleiotrophin plays an important role in the pathogenesis of DR with retinal vascular leakage, ROP with retinal neovascularization and nAMD with choroidal neovascularization. The results also support pleiotrophin as a promising target for anti-angiogenic therapy.

Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development

“…Other alterations of BBB such as pericyte dysfunction at the neurovascular unit have been linked with aberrant angiogenesis (Sweeney et al, 2016). As PTN is known to modulate the astrocytic response in different contexts and to play a role in vascular formation (Martin et al, 2013; Zhang et al, 2014; Wang et al, 2017; Fernandez-Calle et al, 2018), a dual function of this cytokine in both angiogenesis and neuroinflammation in these conditions should not be ruled out.…”

Secretogranin III: a diabetic retinopathy-selective angiogenic factor

“…Furthermore, comparative ligandomics identified pleiotrophin as a DR-high angiogenic factor, albeit with relatively low disease selectivity (38:0 for diabetic:control) [3]. The therapeutic potential of pleiotrophin for DR and ROP was demonstrated in a recent study using pleiotrophin-neutralizing antibodies [111]. These findings suggest that comparative ligandomics is capable of identifying different disease-selective angiogenic factors to facilitate biologic drug discovery and development.…”

Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway

“…Endothelial cell transwell migration assay was carried out, as recently described [9]. Briefly, HUVECs were pretreated with MEK inhibitor PD98059 (10 μM), ERK inhibitor SCH772984 (500 nM) or mock control for 2 h, and collected with trypsin/EDTA digestion.…”