PDGF-C and PDGF-D in ocular diseases

Molecular Aspects of Medicine xxx (2017) 1e11

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PDGF-C and PDGF-D in ocular diseases Anil Kumar, Xuri Li* State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 54 South Xianlie Road, Guangzhou 510060, Guangdong, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 September 2017 Accepted 23 October 2017 Available online xxx

PDGFs and their receptors are critical regulators of numerous tissues and organs, including the eye. Extensive studies have shown that PDGFs and their receptors play critical roles in many ocular neovascular diseases, such as neovascular age-related macular degeneration, retinopathy of prematurity, and proliferative vitreoretinopathy. In addition, PDGFs and PDGFRs are also important players in ocular diseases involving the degeneration of retinal neuronal and vascular cells, such as glaucoma and retinitis pigmentosa. Due to their critical roles in the pathogenesis of many blinding ocular diseases, the PDGFs and PDGFRs have been considered as important target molecules for the treatment of eye diseases. PDGF-C and PDGF-D are relatively new members of the PDGF family and are potent angiogenic and survival factors. Recent studies have demonstrated their important roles in different types of eye diseases. Thus, modulating PDGF-C and PDGF-D activities may have therapeutic values for the treatment of ocular neovascular and degenerative diseases. This review mainly summarizes the recent advances on PDGF-C and PDGF-D biology in relationship to some major ocular diseases. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Platelet-derived growth factor (PDGF) Proliferative vitreoretinopathy Neovascular age-related macular degeneration Retinal pathology Angiogenesis Ischemia-induced retinopathy Inflammation

Introduction The Platelet-derived growth factor (PDGF) family includes PDGF-A, PDGF-B, PDGF-C and PDGF-D. PDGF-A and PDGF-B were discovered in the 1970s (Betsholtz et al., 1986; Doolittle et al., 1983; Heldin et al., 1986; Johnsson et al., 1982; Kohler and Lipton, 1974; Westermark and Wasteson, 1976) from platelets as peptides that can increase the proliferation of smooth muscle cells (Seifert et al., 1984). PDGF-C and PDGF-D, however, are the relatively new PDGF family members identified in 2000 and 2001 respectively (Andrae et al., 2008; Bergsten et al., 2001; LaRochelle et al., 2001; Li et al., 2000). The PDGF family members are potent mitogens secreted by different types of cells, including vascular endothelial cells, vascular smooth muscle cells, pericytes, fibroblasts, mesenchymal cells, epithelial cells, astrocytes, and macrophages. Together, the PDGFs make four homodimers, PDGF-AA, PDGF-BB, PDGF-CC and PDGFDD, and a single heterodimeric polypeptide PDGF-AB. The PDGFs use the platelet derived growth factor receptors (PDGFRs) to exert their diverse functions under physiological or pathological conditions (Kazlauskas, 2017; Li and Eriksson, 2003; Reigstad et al.,

2005). There are two homodimers of the PDGFRs, PDGFR-aa and PDGFR-bb, and one heterodimeric form PDGFR-ab. All PDGF family members and their receptors are expressed in the central nervous system (Hamada et al., 2002), including the retina in the eye, an extended part of the CNS. Particularly, PDGF-C and PDGF-D are abundantly expressed in the retina and retinal pigment epithelial (RPE) cells (Ray et al., 2005). Extensive studies have shown that the PDGFs and their receptors play critical roles in many ocular neovascular diseases, such as proliferative vitreoretinopathy (PVR), retinopathy of prematurity (ROP), and neovascular age-related macular degeneration (NVAMD) (Witmer et al., 2003), which are associated with dysfunctions of multiple components, such as blood vessels, inflammatory cells and RPE cells. Moreover, the PDGFs and PDGFRs are also important players in ocular pathologies involving the degeneration of retinal ganglion cells and photoreceptors, such as in glaucoma and retinitis pigmentosa (RP) (Berger et al., 2010). Due to their critical roles in the pathogenesis of many ocular diseases, the PDGFs and PDGFRs have been considered as important target molecules for the treatment of eye diseases. Roles of PDGF-C and PDGF-D in proliferative vitreoretinopathy

* Corresponding author. E-mail address: [email protected] (X. Li).

PVR is a blinding disease resulted from rhegmatogenous retinal detachment following retinal reattachment surgery (Pastor et al.,

https://doi.org/10.1016/j.mam.2017.10.002 0098-2997/© 2017 Elsevier Ltd. All rights reserved.

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2016) (Fig. 1). PVR is characterized by the outgrowth of the inner and outer membranes of the retina. This leads to the formation of fibrovascular membranes, which ultimately causes retinal scaring and traction (Pennock et al., 2014). PVR can arise before surgery, but is more common after surgical procedures (Claes and Lafeta, 2014). It has been estimated that PVR occurs in about 5e10% of all retinal detachment cases (Pastor et al., 2016). Current therapeutic interventions for PVR include surgeries such as scleral buckling, membrane peeling, pars plana vitrectomy, and pneumatic retinopexy. However, all these procedures impair visual acuity significantly due to damage to the retinae (Coffee et al., 2014; Sadaka and Giuliari, 2012). Other therapeutic options include anti-inflammatory drugs (Cheema et al., 2007), antiproliferative reagents (Charteris et al., 2004), and antineoplastic drugs (Hou et al., 2015). However, these drugs are not able to impede the progression of the disease effectively. Numerous studies have shown that the pathogenesis of PVR is orchestrated by multiple aspects, such as growth factors (Charteris,

1998; Wubben et al., 2016), cytokines (Harada et al., 2006; Limb et al., 1991), extracellular matrix proteins (Feist et al., 2014) and various cellular interactions (Pennock et al., 2011). Importantly, clinical studies have demonstrated the presence of PDGFs in human vitreous samples of PVR patients (Akiyama et al., 2006; Andrews et al., 1999; Lei et al., 2007, 2011; Lei and Kazlauskas, 2014; Mori et al., 2002; Pastor et al., 2016; Si et al., 2013). Moreover, activated PDGF receptors have been found on the epiretinal membranes of PVR patients (Cui et al., 2009). Noteworthy, one of the most abundant vitreal growth factors detected in both experimental PVR models and PVR patients is PDGF-C (Lei et al., 2007). Indeed, both PDGF-C and PDGF-D have been shown to promote the proliferation and migration of RPE cells (Li et al., 2007) (Fig. 1). Moreover, studies using animal model have shown that PDGF-C promotes ECM production and remodeling via PDGFR-a (Wiradjaja et al., 2013). In addition, in PVR, a critical pathology is the transformation of RPE cells into fibroblast-like cells via epithelial-mesenchymal transition (EMT) (Bastiaans et al., 2013).

Fig. 1. PDGF-C signaling in proliferative vitreoretinopathy (PVR). The human retina is highly laminated. Inset box a shows that in a cross section view, the retina is embraced with superior nerve fibre layer, retinal ganglion cells, radial Müller cells, amacrine cells, bipolar cells, horizontal cells, rod cells, cone cells, retinal pigment epithelial cells, and choriocapillaris. Repeating retinal detachment steers the retinal tear and compromises the retinal integrity, which subsequently triggers the production of various growth factors and proteases to initiate the wound healing process with damaged gliotic MCs, apoptotic RGCs, invading RPE cells and other retinal cells. Inset box b shows that elevated levels of PDGF-C activate PDGF receptor alpha signaling, which promotes transcriptional changes to enforce cell differentiation, proliferation, migration, survival, epithelial mesenchymal transition and extracellular remodeling. Inset box c shows that in a cross section view of the retina with PVR, the otherwise stationary RPE cells are highly differentiated and migrate towards the nerve fibre layer. The presence and potential role of PDGF-D in PVR remain to be investigated. NFL: nerve fibre layer, RGC: retinal ganglion cell, AC: amacrine cell, MC: Müller cell, BC: bipolar cell, HC: horizontal cells, R: rod cell, C: cone cell, RPE: retinal pigment epithelial cell, CC: choriocapillary.

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PDGF family members have been shown to promote EMT alone (Smith et al., 2011; Yang et al., 2006) or involving transforming growth factor-b signaling, which is a known potent EMT inducer (Li et al., 2011). The potential role of PDGF-C in EMT remains to be investigated. However, by enhancing the proliferation and migration of RPE cells into the inner neurosensory retina (Fig. 1), by promoting fibrovascular growth, and by increasing the production of extracellular matrix, PDGF-C plays an important role in PVR. PDGF-C has been shown to display pleiotropic effects on multiple cellular targets, including both vascular and non-vascular cells, such as endothelial cells, mural cells, astrocytes, fibroblasts, and macrophages (Lee et al., 2013). Indeed, immunohistochemically analysis of PVR membranes highlighted the presence of both PDGFR-a and PDGFR-b on them (Cui et al., 2009; Robbins et al., 1994). Moreover, in PVR, phosphorylated PDGFR-a has been shown to be more abundant compared with phosphorylated PDGFR-b, suggesting the involvement of PDGF-C and PDGFR-a signaling in the pathogenesis of PVR (Lei and Kazlauskas, 2014). Interestingly, the presence of plasmin has been shown in the vitreous of rabbits and patients that underwent surgery (Lei and Kazlauskas, 2008). Since plasmin can proteolytically generate the active form of PDGF-C from its latent form, this further supports the contribution of PDGF-C to the pathological process of PVR (Fredriksson et al., 2004; Lei et al., 2008). Moreover, it has been also shown that PDGFR-a can be highly activated by the reactive oxygen species generated during PVR (Lei and Kazlauskas, 2014). Therefore, studies have shown that PDGF-C and its cognate receptor PDGFR-a may be effective therapeutic targets for the treatment of PVR. PDGF-D binds to and activates PDGFR-b, which is highly expressed in PVR. Therefore, PDGF-D may play a role in the pathogenesis of PVR as well. However, future studies are needed to verify this. PDGF-C and PDGF-D in ischemia-induced retinopathy Blood vessels are essential for the normal function and homeostasis of the retinae by providing oxygen, nutrients, and metabolic exchange (Anand-Apte et al., 2010). Any defect or disruption of the vascular system will impair the delivery of oxygen and nutrients through the blood supply to the energy utilizing retinal cells and leads to retinal ischemia (Moran et al., 2016). As a consequence, the oxygen-deprived and starving retinal cells upregulate angiogenic and growth factors to promote blood vessel growth, which can in turn result in ischemia-induced retinopathies, such as diabetic retinopathy, NV-AMD, and ROP. ROP is a potentially blinding disease that occurs primarily in premature infants. In ROP, abnormal blood vessels grow into the retina and cause it to detach from the back of the eye, when uncontrolled, leading to blindness. ROP is one of the most common causes of visual loss in childhood globally and can lead to lifelong vision impairment or blindness (Liegl et al., 2016; Zin and Gole, 2013). In middle- and low-income countries, the incidence of ROP is over 40% (Rivera et al., 2017; Zin and Gole, 2013). However, in high-income countries, the incidence of ROP is reported to be less than 10%. The development of ROP is characterized initially by delayed retinal vascular development (Cayabyab and Ramanathan, 2016). This results in retinal ischemia, which subsequently leads to vascular proliferation and abnormal growth of retinal blood vessels (Smith, 2004). Clinical studies using ocular fluid from ROP patients have implicated roles of proangiogenic factors in the development of ROP (Liegl et al., 2016). Such proangiogenic factors include cytokines (Hartnett, 2017), chemokines (Powers et al., 2005), and growth factors, including vascular endothelial growth factor (VEGF) (Kandasamy et al., 2017), fibroblast growth factor (Sato et al., 2009) and PDGFs (Tolentino, 2009). Current treatments for ROP include laser therapy and

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cryotherapy (Hartnett, 2003; Long, 1989; McNamara et al., 1991). Both procedures are invasive and destroy the peripheral retinae, thus impairing some side vision. For late stage ROP, available treatments include scleral buckle and vitrectomy. When the center of the retina or the entire retina detaches, surgery is needed to reattach the retina. In recent years, researchers have tested antiVEGF therapies for the treatment of ROP, and inhibition of retinal neovascularization has been observed (Jin et al., 2017; Sankar et al., 2016). However, the data are not sufficient to draw conclusions on other critical outcomes and potential long-term systemic adverse effects. Moreover, it is known that VEGF is required for the normal development of the neurovascular system of preterm infants (Patel et al., 2016). Therefore, inhibition of VEGF requires caution since it might impede the normal development of retinal vasculature and neurons. In summary, further studies are required to investigate the effects of anti-VEGF drugs on the retinae and any potential delayed systemic side effects (Sankar et al., 2016). The roles of the PDGFs in ROP have been reported by several studies. It has been shown that intraocular injection of anti-PDGFBB DARPins (designed ankyrin repeat proteins), a recombinant protein with ankyrin repeats of conserved and variable amino acids, strongly suppressed ischemia-induced retinal neovascularization (Dong et al., 2014). However, another study showed different results. In a rat model of ischemic retinopathy, inhibition of PDGF receptor tyrosine kinase (RTK) by STI571 (Gleevec), a potent inhibitor of PDGF RTK, led to pericyte loss and increased retinal angiogenesis (Wilkinson-Berka et al., 2004), supporting that PDGFs are required for the survival of pericytes, which are required to prevent VEGF/VEGFR-2 upregulation in ROP. PDGF-C and PDGF-D are produced by multiple types of ocular cells, including RPE cells (Li et al., 2007), endothelial cells (Karvinen et al., 2009), fibroblasts (Crawford et al., 2009), macrophages (Wagsater et al., 2009), pericytes and vascular smooth muscle cells (Gilbertson et al., 2001). The cognate tyrosine kinase receptors for PDGF-C and PDGF-D, PDGFR-a and PDGFR-b, are expressed by mural cells (Sundberg et al., 1993), RPE cells (Vinores et al., 1995), fibroblasts (Borkham-Kamphorst et al., 2015), macrophages (Savikko and von Willebrand, 2001), and retinal neuronal cells (Tang et al., 2010). Thus, the expression of PDGF-C and PDGF-D and their cognate receptors on many types of ocular cells suggests that they may have important functions in ROP. Indeed, the roles of PDGF-C and PDGF-D in ROP have been reported (Hou et al., 2010; Kumar et al., 2010). In an oxygen-induced retinopathy model (Fig. 2), treatment of the neonatal mice from postnatal day 7e12 (P7-P12) with hyperoxia leads to a severe regression of retinal blood vessels (Smith et al., 1994). This subsequently results in retinal hypoxia and retinal neovascularization during P12-P17. In this model, targeting PDGF-C and PDGF-D by neutralizing antibodies or shRNA reduced the formation of retinal vascular tufts (Hou et al., 2010; Kumar et al., 2010). Indeed, this observation was confirmed in a mouse model of ROP using PDGF-C deficient mice (Hou et al., 2010). At a gene expression level, loss of PDGF-C decreased the expressions of many proangiogenic genes, such as fibroblast growth factor-2, Vegf-b, placental growth factor, and Vegf, and increased the expressions of many proapoptotic genes, including decorin and tumor necrosis factor-a, which inhibits PDGFinduced proliferation and migration of vascular cells (Hou et al., 2010). Moreover, PDGF-D knockdown by shRNA inhibited retinal neovascularization and decreased the expressions of HIF1a, Has, and Vegf-b in mouse eyes (Kumar et al., 2010). Furthermore, gene silencing of PDGF-D upregulated the expressions of many proapoptotic genes, such as Olr-1, a potent vascular apoptosis inducer, tumor necrosis factor-a, and decorin (Kumar et al., 2010). Mechanistically, it has been shown that glycogen synthase kinase3b acts as a downstream effector mediating the angiogenic effects

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Fig. 2. PDGF-C and PDGF-D in retinopathy of prematurity. In healthy new-borns, various growth fostering factors promote the development of retina blood vessels. Inset box a shows a cross section view of normal retina. It demonstrates that retinal blood vessels branch into three layers in the retina: superficial layer, intermediate layer and deep vascular plexus. Inset box b shows that in preterm infants, poor retinal blood vessel development leads to hypoxia. Or, a hyperoxic environment suppresses the availability of angiogenic factors, and subsequently, the metabolically demanding retinal cells become hypoxic and in turn upregulate the levels of angiogenic factors, which consequently induce pathological retinal neovascularization. PDGF-C and PDGF-D are among such angiogenic factors secreted by the hypoxic retinal cells. Key pathologies of retinopathy of prematurity include the formation of superficial vascular tufts and the avascular area in the central retina. BV: blood vessel, RGC: retinal ganglion cell, AC: amacrine cell, MC: Müller cell, BC: bipolar cell, HC: horizontal cells, PC: photoreceptor cell, RPE: retinal pigment epithelial cell, CC: choriocapillary.

of PDGF-C and PDGF-D (Hou et al., 2010; Kumar et al., 2010). Importantly, since the cellular targets of PDGF-C are largely different from those of VEGF, the PDGF-C-induced angiogenesis is therefore to a great extent independent of VEGF pathway (Li et al., 2010). Thus, targeting PDGF-C and PDGF-D may have therapeutic usage for the treatment of ROP. Roles of PDGF-C and PDGF-D in neovascular age-related macular degeneration (NV-AMD) AMD is the leading cause of irreversible blindness in aged population worldwide (Bird, 2010; Gelfand and Ambati, 2016; Miller, 2013). Results of a meta-analysis show that about 8.7% of the world's population has AMD (Wong et al., 2014). By 2020, the number of people with AMD is expected to reach 196 million worldwide and has been estimated to touch 288 million by 2040 (Wong et al., 2014). Numerous factors are involved in the

pathogenesis of AMD. However, age is the most prominent risk factor associated with AMD, followed by genetic and environmental factors and lifestyle (Fritsche et al., 2014; Hammond et al., 2002; Rudnicka et al., 2015; Sobrin and Seddon, 2014). People between 50 and 59 years old has a 2% risk of developing AMD. For those over 75 years old, the risk increases to 30% (Klein et al., 1992, 2010). AMD can be classified into early and late stages (Ambati et al., 2003; Ferris et al., 2013). Early AMD is also known as dry AMD (Bowes Rickman et al., 2013; Narayanan and Kuppermann, 2017) and is characterized by the accumulation of lipoproteins and cellular debris between the basal lamina of RPE cells and the inner layer of Bruch's membrane, which ultimately leads to photoreceptor degeneration (Curcio et al., 2005, 2011; Wang et al., 2010). Dry AMD accounts for about 90% of the AMD cases diagnosed. About 10% of dry AMD develop into late stage AMD (Ferris et al., 2013). Clinically, late stage AMD can be either exudative (wet AMD) or has geographic atrophy (Brucker, 2009; Ferris et al., 2013;

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Sunness et al., 1999). Wet AMD is also called neovascular AMD (NVAMD). In NV-AMD, abnormal blood vessels grow from the choroids into the subretinal space in response to the extensive damage of the pigment epithelial layer of the macula due to the presence of drusen. The fragile neovessels are disorganized and leaky, leading to swelling and damage of the macula (Hartnett et al., 1992; Miller, 2013). Even though NV-AMD accounts for only about 10% of AMD patients, they are responsible for most cases of blindness. There are several therapeutic options for AMD management. The first generation of therapies include laser and photodynamic treatments (study, 1986). In 2004, the first antiangiogenic drug for AMD treatment, Pegaptanib (Macugen), was approved by FDA. This symbolizes the beginning of the second generation of therapies for AMD using anti-VEGF treatment. Pegaptanib is a single strand RNA aptamer that binds specifically to VEGF and inhibits its function (Ng and Adamis, 2006; Ng et al., 2006). Encouraged by this success, other types of VEGF inhibitors were soon developed and have been shown to be more effective in inhibiting choroidal neovascularization in NV-AMD. Ranibizumab (Lucentis) is a monoclonal antibody fragment that binds to all VEGF isoforms (Bressler et al., 2010; Rosenfeld et al., 2006). Aflibercept (Eylea) is a recombinant protein containing the extracellular domains of VEGFR1 and VEGFR2, which binds to all isoforms of VEGF, VEGF-B, and PlGF (Villegas et al., 2017). Conbercept is a recombinant protein containing the second Ig domain of VEGFR1 and the third and fourth Ig domains of VEGFR2 fused to the Fc part of human IgG1 (Peng et al., 2017; Xu et al., 2017). Currently, they are the premier treatments for NV-AMD in the clinic. Despite the great success of anti-VEGF therapy (Ferrara, 2016), there exist many challenges. For example, drug resistance to antiVEGF therapy has emerged to be a serious problem (Eichten et al., 2016). The effect of anti-VEGF therapy declines in most patients within the first four years of treatment (Jaffe et al., 2016). Moreover, not all patients with NV-AMD are responsive to antiVEGF therapy (Crawford and Ferrara, 2009), suggesting the existence of other important angiogenic components. Indeed, tremendous efforts have been made in the field to identify new targets for antiangiogenic therapy. One such example has been the development of Fovista, a PDGF-B inhibitor. However, in phase three clinical trials, combination therapy of Fovista with anti-VEGF treatment failed to improve vision in patients with NV-AMD (Dunn et al., 2017; Jaffe et al., 2017), suggesting a more complex scenario of pathological angiogenesis in NV-AMD than previously anticipated. Inflammation features prominently in NV-AMD (Ambati et al., 2013) and other retinopathies (Capitao and Soares, 2016; Rivera et al., 2017). Although acute inflammation is beneficial for tissue defense and repair, chronic inflammation leads to tissue damage and triggers cell death (Chovatiya and Medzhitov, 2014). Microglia, monocytes, and macrophages are the inflammatory cells known to play critical roles in pathological angiogenesis (Kumar et al., 2014; Ma and Wong, 2016). Microglial cells activated in diabetic retinopathy and ROP are believed to play significant roles in these pathologies (Zeng et al., 2008). In NV-AMD, macrophages contribute to pathological neovascularization at least partially by producing various proangiogenic molecules, such as growth factors, chemokines, cytokines, and proteases (Miao et al., 2012; Miller et al., 2013; Rutar and Provis, 2016). The roles of PDGF-C and PDGF-D in NV-AMD have been shown by many studies. In animal models of laser injury-induced NVAMD, the expressions of PDGF-C and PDGF-D are upregulated (Hou et al., 2010; Kumar et al., 2010). In a mouse model of choroidal neovascularization (CNV) (Fig. 3), Pdgf-c gene deletion decreased CNV formation and reduced the numbers of infiltrated macrophages, signifying decreased inflammation (Hou et al., 2010). Consistently, inhibition of PDGF-C or PDGFR-a by their neutralizing

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antibodies also inhibited CNV formation and reduced the number of infiltrating macrophages in mice (Hou et al., 2010). Indeed, it has been shown that PDGF-C has a direct effect on macrophages by promoting their migration and proliferation (Hou et al., 2010; Son et al., 2014; Yang et al., 2010). In addition, it has been shown that PDGF-C promotes the formation of fibrovascular scaffolds by promoting the proliferation, migration, and survival of mural cells, which are conventionally known to be the major cellular targets of PDGFs (Hou et al., 2010). Moreover, PDGF-C exerts its angiogenic effect by upregulating the expressions of Vegf, Pdgf-b, and Pdgfr-b, which are all proangiogenic. Indeed, blocking PDGF-C signaling with a neutralizing antibody reduced their expression in a mouse model of NV-AMD (Hou et al., 2010). PDGF-D has been shown to act on a wide range of cell types (Bergsten et al., 2001; Ponten et al., 2005; Ray et al., 2005). Also, PDGF-D can be produced by many cell types, such as vascular cells and macrophages (Bergsten et al., 2001; Reigstad et al., 2005). PDGF-D has been shown to be a potent chemoattractant to macrophages (Uutela et al., 2004). Moreover, the receptors used by PDGF-D, PDGFR-b and neuropilin (NRP) 1, are expressed by macrophages and microglia (Dai et al., 2017; Dejda et al., 2016; Muhl et al., 2017). PDGF-D thus has a direct effect on macrophages and microglia. Moreover, PDGF-D has been shown to induce the proliferation and migration of multiple cell types, including choroidal fibroblasts and vascular pericytes. Thus, plenty of data have suggested important roles of PDGF-D in NV-AMD. Indeed, PDGF-D has been shown to be up-regulated in the neovascular choroid and retina (Kumar et al., 2010). Importantly, in an experimental NVAMD mouse model, silencing of PDGF-D by short hairpin (sh) RNA or its neutralizing antibody suppressed both retinal and choroidal neovascularization in mice (Kumar et al., 2010). In addition, inhibition of PDGF-D decreased the number of infiltrated macrophages during CNV formation. Mechanistically, it has been shown that PDGF-D regulates the phosphorylation of its downstream effector, glycogen synthase kinase-3b, via PDGFR-b (Kumar et al., 2010). Thus, based on the potent angiogenic effect of PDGF-D, it may serve as a promising target molecule for antiangiogenic therapy for the treatment of NV-AMD. Neuro- and vaso-protective effects of PDGF-C and PDGF-D in retinitis pigmentosa RP is an inherited and heterogeneous degenerative retinal dystrophy that causes severe vision impairment due to the progressive degeneration of the rod photoreceptor cells in the retina (Hartong et al., 2006). In the early stage of RP, peripheral and dim light vision compromise due to the decline of rod photoreceptors. The progressive rod degeneration is later followed by abnormalities in the retinal blood vessels (Adamus et al., 2012; Liu et al., 2016), retinal pigment epithelium and the deterioration of cone photoreceptor cells (Ali et al., 2017). As peripheral vision becomes increasingly compromised, patients experience progressive ““tunnel vision” and eventual blindness. The incidence of RP is about 1 in 3000e7000 people. More than 1.5 million individuals are affected worldwide (Ferrari et al., 2011). RP can be inherited as an autosomal dominant, autosomal recessive, or X-linked disease (Daiger et al., 2007; Hartong et al., 2006). More than 250 genes have been identified to be associated with this progressive degenerative disease (Retinal information network, https://sph.uth.edu/retnet/sum-dis.htm#A-genes). Currently, there are no effective treatments for RP. Dietary supplementation with vitamin A palmitate and fish oil, which is rich in omega 3 fatty acids, have been recommended to help slow down the progression of the disease (Parmeggiani et al., 2011). In addition, preclinical studies have shown that gene therapy might be a plausible approach for the treatment of RP. For example, in AiP1

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Fig. 3. PDGF-C and PDGF-D in choroidal neovascularization. Inset box a shows that the normal outer retina consists photoreceptor cells (rods and cones) and the RPE layer, which are nourished by choroidal blood vessels. Inset box b shows that under pathological conditions, the expression of proangiogenic factors, including PDGF-C and PDGF-D, are upregulated and promote the outgrowth of new blood vessels from the existing choriocapillaris. The neovessels breach the Bruch's membrane underneath the RPE cells and invade into the neural retina, leading to oedema, retinal detachment, and photoreceptor degeneration. At least in part, PDGF-C and PDGF-D promote neovascularization by recruiting inflammatory cells. Activated retinal microglia and choroidal macrophages are known to play important roles in choroidal neovascularization. BV: blood vessel, RGC: retinal ganglion cell, AC: amacrine cell, MC: Müller cell, BC: bipolar cell, Mi: microglia, HC: horizontal cells, R: rod cell, C: cone cell, RPE: retinal pigment epithelial cell, CC: choriocapillary, CNV: choroidal neovascularization, a-Mi: activated microglia, a-Mac: activated macrophage.

mutant mice, successful rescuing of retinal denegation by AIPL1 gene delivery using AAV virus (AAV-hAIPL1) has been shown (Ku et al., 2015). Moreover, using dogs with Pde6a mutation, it has been shown that subretinal injection of virus encoding the gene Pde6a (AAV-Pde6a) improved dim light vision and cone photoreceptor survival (Mowat et al., 2017). This success of Pde6a gene therapy for retinitis pigmentosa in a large animal model prompts further studies on gene therapy in RP patients. Although PDGFs and PDGFRs are abundantly expressed in the retina (Andrae et al., 2008; Biswas et al., 2008; Kanamoto et al., 2011; Wilkinson-Berka et al., 2004), their potential roles in RP have not been well studied. However, studies have shown that PDGF-C is a potent neuroprotective factor and a vascular survival factor (Cai et al., 2016; Lee et al., 2013; Peng et al., 2012; Tang et al., 2010). In addition,

PDGF-C has been shown to act on multiple cell types by regulating the expression of heme oxygenase-1, which is a potent antioxidant and anti-inflammatory factor (Chung et al., 2008; Wegiel et al., 2014). These observations thus have suggested protective and surviving roles of PDGF-C in RP. Indeed, in a mouse model of RP, it has been shown that the degeneration of both vascular and non-vascular cells of the neurosensory retina can be partially restored by PDGF-CC protein treatment (Fig. 4) (He et al., 2014). Additionally, PDGF-CC delivery preserved the architecture of retinal layers by reducing focal retinal lesions and attenuating the loss of photoreceptors in a mouse model of RP (He et al., 2014). This effect of PDGF-CC is at least partially medicated by downregulating the expression of some proapoptotic molecules such as Fas ligand and Bax (He et al., 2014). Consistently, it has also been shown that in a mouse model of

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Fig. 4. Neuroprotective effect of PDGF-C in retinitis pigmentosa. (a) Normal retina is well organised into several layers containing blood vessels, neuronal cells and other cell types. Different retinal cells are functionally and structurally interconnected to process the visual perception. (b) In retinitis pigmentosa, photoreceptor degeneration occurs, leading to the impairment of retinal structure, tissue remodeling, displacement of inner retinal cells, gliosis of MC and vascular degeneration. (c) Results from preclinical studies show that intravitreal injection of PDGF-CC protein rescues photoreceptor and vascular degeneration in a RP model. The potential role of PDGF-D in RP remains to be investigated. BV: blood vessel, RGC: retinal ganglion cell, AC: amacrine cell, MC: Müller cell, BC: bipolar cell, Mi: microglia, HC: horizontal cells, R: rod cell, C: cone cell, RPE: retinal pigment epithelial cell, RP: retinitis pigmentosa.

oxygen-induced blood vessel regression, PDGF-CC treatment prevented the regression of retinal blood vessels (He et al., 2014). Taken together, these data show that PDGF-CC may have a therapeutic potential in RP treatment by promoting neuronal and vascular cell survival. Anti-apoptotic effect of PDGF-C and PDGF-D in glaucoma Glaucoma is the second leading ocular disease worldwide (Kingman, 2004; Quigley, 1996). The global prevalence of glaucoma is over 57 million individuals in 2015. It is estimated to reach over 111 million by 2040 (Kapetanakis et al., 2016). The increase of intra ocular pressure (IOP) is believed to be the main cause of this progressive and chronic neurodegenerative disorder. In glaucoma, extensive extracellular remodeling of the trabecular meshwork is one of the reasons leading to increased IOP. Also, myofibroblasts are activated in glaucoma and drive the formation of tissue fibrosis and stiffening (Liu et al., 2017). Loss of retinal ganglion cells and deformation of the optic nerve head are the hallmarks of glaucoma (Burgoyne et al., 2005).

Clinically, glaucoma can be classified into four categories, including primary open angle glaucoma, secondary open angle glaucoma, primary angle closure glaucoma and primary congenital glaucoma (Foster et al., 2002). Currently, topical eye drops and oral medications that can lower IOP are used to treat glaucoma. Such drugs include b-adrenergic antagonists, prostaglandin analogues, adrenergic agonists, carbonic anhydrase inhibitors and cholinergic agonists (Alward, 1998). Despite the existing drugs, therapies that can lower IOP more effectively and rescue the progressive neurodegeneration without adverse effects are yet to be realized. In addition to IOP-lowering drugs, surgical procedures including laser surgery, trabeculectomy (Rosenquist et al., 1989) and drainage implant surgery (Guerrero and Latina, 2000) are being used for the long-term management of glaucoma. Furthermore, various approaches aiming at rescuing neurodegeneration in glaucoma have been tested in preclinical models. These include intravitreal delivery of stem cells (Venugopalan et al., 2016), neurotrophic factors such as BDNF (Ko et al., 2001), CNTF (Ji et al., 2004) and gene therapy (Wilson and Di Polo, 2012).

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Studies have shown the roles of PDGFs and PDGFRs in glaucoma. It is reported that PDGFR-a is expressed in retinal ganglion cell layer and is critical for the survival of retinal cells under oxidative stress (Kanamoto et al., 2011). Recently, it has been shown that PDGF-AA protein treatment rescues retinal ganglion cells from death in mice expressing enhanced green fluorescent protein (EGFP) under PDGFR-a promoter (Takahama et al., 2017). It has also been shown that PDGFR-a is expressed in the inner nuclear layer and ganglion cell layer (Takahama et al., 2017). Moreover, PDGF signaling pathway has been shown to be implicated in the pathogenesis of primary open angle glaucoma (Colak et al., 2012). Additionally, it has been reported that PDGF-AB and PDGF-BB are detected in the aqueous humor of patients with uveitic glaucoma, also suggesting their potential roles in glaucoma (Ohira et al., 2016). PDGF-C and its receptors are highly expressed in the retina (Tang et al., 2010). Preclinical studies using animal models have shown that PDGF-CC protein or gene delivery rescued ganglion cells in the retina in an axotomy-induced neuronal injury model and a neurotoxin-induced retinal neuronal death model (Tang et al., 2010). Moreover, PDGF-CC treatment also decreased stroke volume and neuronal apoptosis in an ischemia-induced stroke model (Tang et al., 2010). Conversely, the loss of PDGF-CC activity by various means, such as genetic deletion, PDGF-CC neutralizing antibody, or shRNA treatment, exacerbated retinal neuronal death in different models in vivo (Tang et al., 2010). The neuroprotective effect of PDGF-CC, at least in part, is exerted by regulating the expression of numerous apoptotic, cell survival and neurotrophic genes. At a molecular level, it has been shown that the phosphorylation of GSK3b is the downstream signaling employed by PDGF-CC for its neuroprotective effect. These findings thus highlight the importance of the neurovascular protective effects of PDGF-CC. The potential role of PDGF-D in glaucoma is thus far unclear. However, it has been recently shown that PDGF-D binds to NRP1, which plays an important role in the neurovascular system (Muhl et al., 2017), thereby suggesting a possible function of PDGF-D in glaucoma. Future studies are needed to verify this. Perspectives and outstanding questions Decades of extensive studies have shown that PDGFs and their receptors are critical players in numerous biological processes. Particularly, they are key regulators of vascular growth and function, neuronal survival, and fibrosis, all of which are critical components of many blinding diseases. Thus, the PDGFs and their receptors have been considered as important therapeutic targets for neurovascular and fibrotic diseases. Indeed, numerous preclinical studies have demonstrated the effectiveness of modulating PDGF pathway in different animal models. However, despite the significant advances, promising laboratory results have not been translated into clinically useful therapies, suggesting that a better and deeper understanding of the functions of PDGFs and PDGFRs and the underlying mechanisms are still needed. Indeed, many outstanding questions remain to be answered. What are the functional differences among the different PDGFs in ocular diseases? What are the relative contributions of the different PDGFs and PDGFRs to different ocular pathologies, particularly, to ocular neovascularization? Combination therapy using Fovista targeting PDGF-B together with anti-VEGF therapy has failed. Would combination therapy targeting other PDGFs together with anti-VEGF treatment work? How are the expressions of the PDGFs and PDGFRs regulated or dysregulated in different ocular diseases? Do current therapies affect their expression and function? How are the functions and signaling pathways of the PDGFs related to the VEGF pathway? Are they functionally independent of each other? Are the angiogenic

activities of the PDGFs related to the development of drug resistance to anti-VEGF therapy? Can the PDGFs be used as biomarkers for the states of ocular diseases or therapeutic outcomes? Are there new receptors or new signaling pathways for the relatively new PDGFs, PDGF-C and PDGF-D? Can the protective and survival effects of PDGFs be used to treat retinal degenerative diseases to preserve different types of retinal cells? Answers to these questions will not only help understand the basic biology of the PDGF family but will also facilitate the process of translating laboratory observations into clinically useful therapies. Acknowledgement This work is supported by the State Key Laboratory of Ophthalmology (SKLO) at the Zhongshan Ophthalmic Center (ZOC), Sun Yat-Sen University (SYSU), Guangzhou, China; a Key Program of the National Natural Science Foundation of China (NSFC, 81330021) to X. Li; an NSFC grant (81670855) to X. Li; an NSFC-Swedish Research Foundation (VR) International Collaboration grant (81611130082) to X. Li; and a Guangdong Province Leading Expert Program grant to X. Li. References Adamus, G., Wang, S., Kyger, M., Worley, A., Lu, B., Burrows, G.G., 2012. Systemic immunotherapy delays photoreceptor cell loss and prevents vascular pathology in Royal College of Surgeons rats. Mol. Vis. 18, 2323e2337. Akiyama, H., Kachi, S., Silva, R.L., Umeda, N., Hackett, S.F., McCauley, D., McCauley, T., Zoltoski, A., Epstein, D.M., Campochiaro, P.A., 2006. Intraocular injection of an aptamer that binds PDGF-B: a potential treatment for proliferative retinopathies. J. Cell. Physiol. 207 (2), 407e412. Ali, M.U., Rahman, M.S.U., Cao, J., Yuan, P.X., 2017. Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario. 3 Biotech. 7 (4), 251. Alward, W.L., 1998. Medical management of glaucoma. N. Engl. J. Med. 339 (18), 1298e1307. Ambati, J., Ambati, B.K., Yoo, S.H., Ianchulev, S., Adamis, A.P., 2003. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv. Ophthalmol. 48 (3), 257e293. Ambati, J., Atkinson, J.P., Gelfand, B.D., 2013. Immunology of age-related macular degeneration. Nat. Rev. Immunol. 13 (6), 438e451. Anand-Apte, B., Hollyfield, J., Clinic, C., 2010. Developmental Anatomy of the Retinal and Choroidal Vasculature. Andrae, J., Gallini, R., Betsholtz, C., 2008. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22 (10), 1276e1312. Andrews, A., Balciunaite, E., Leong, F.L., Tallquist, M., Soriano, P., Refojo, M., Kazlauskas, A., 1999. Platelet-derived growth factor plays a key role in proliferative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 40 (11), 2683e2689. Bastiaans, J., van Meurs, J.C., van Holten-Neelen, C., Nijenhuis, M.S., KolijnCouwenberg, M.J., van Hagen, P.M., Kuijpers, R.W., Hooijkaas, H., Dik, W.A., 2013. Factor Xa and thrombin stimulate proinflammatory and profibrotic mediator production by retinal pigment epithelial cells: a role in vitreoretinal disorders? Graefe's Arch. Clin. Exp. Ophthalmol. ¼ Albr. Graefes Arch. Klin. Exp. Ophthalmol. 251 (7), 1723e1733. Berger, W., Kloeckener-Gruissem, B., Neidhardt, J., 2010. The molecular basis of human retinal and vitreoretinal diseases. Prog. Retin. eye Res. 29 (5), 335e375. Bergsten, E., Uutela, M., Li, X., Pietras, K., Ostman, A., Heldin, C.H., Alitalo, K., Eriksson, U., 2001. PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat. Cell Biol. 3 (5), 512e516. Betsholtz, C., Johnsson, A., Heldin, C.-H., Westermark, B., Lind, P., Urdea, M.S., Eddy, R., Shows, T.B., Philpott, K., Mellor, A.L., Knott, T.J., Scott, J., 1986. cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines. Nature 320 (6064), 695e699. Bird, A.C., 2010. Therapeutic targets in age-related macular disease. J. Clin. Invest. 120 (9), 3033e3041. Biswas, S.K., Zhao, Y., Nagalingam, A., Gardner, T.W., Sandirasegarane, L., 2008. PDGF- and insulin/IGF-1-specific distinct modes of class IA PI 3-kinase activation in normal rat retinas and RGC-5 retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 49 (8), 3687e3698. Borkham-Kamphorst, E., Alexi, P., Tihaa, L., Haas, U., Weiskirchen, R., 2015. Plateletderived growth factor-D modulates extracellular matrix homeostasis and remodeling through TIMP-1 induction and attenuation of MMP-2 and MMP-9 gelatinase activities. Biochem. Biophys. Res. Commun. 457 (3), 307e313. Bowes Rickman, C., Farsiu, S., Toth, C.A., Klingeborn, M., 2013. Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging. Invest.

Please cite this article in press as: Kumar, A., Li, X., PDGF-C and PDGF-D in ocular diseases, Molecular Aspects of Medicine (2017), https://doi.org/ 10.1016/j.mam.2017.10.002

A. Kumar, X. Li / Molecular Aspects of Medicine xxx (2017) 1e11 Ophthalmol. Vis. Sci. 54 (14), ORSF68eORSF80. Bressler, N.M., Chang, T.S., Suner, I.J., Fine, J.T., Dolan, C.M., Ward, J., Ianchulev, T., Marina, Groups, A.R., 2010. Vision-related function after ranibizumab treatment by better- or worse-seeing eye: clinical trial results from MARINA and ANCHOR. Ophthalmology 117 (4), 747e756 e744. Brucker, A.J., 2009. Age-related macular degeneration. Retina 29 (6 Suppl. l), S2eS4. Burgoyne, C.F., Downs, J.C., Bellezza, A.J., Suh, J.K., Hart, R.T., 2005. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog. Retin. Eye Res. 24 (1), 39e73. Cai, Y., Yang, L., Hu, G., Chen, X., Niu, F., Yuan, L., Liu, H., Xiong, H., Arikkath, J., Buch, S., 2016. Regulation of morphine-induced synaptic alterations: role of oxidative stress, ER stress, and autophagy. J. Cell Biol. 215 (2), 245e258. Capitao, M., Soares, R., 2016. Angiogenesis and inflammation crosstalk in diabetic retinopathy. J. Cell. Biochem. 117 (11), 2443e2453. Cayabyab, R., Ramanathan, R., 2016. Retinopathy of prematurity: therapeutic strategies based on pathophysiology. Neonatology 109 (4), 369e376. Charteris, D.G., 1998. Growth factors in proliferative vitreoretinopathy. Br. J. Ophthalmol. 82 (2), 106. Charteris, D.G., Aylward, G.W., Wong, D., Groenewald, C., Asaria, R.H., Bunce, C., Group, P.V.R.S., 2004. A randomized controlled trial of combined 5-fluorouracil and low-molecular-weight heparin in management of established proliferative vitreoretinopathy. Ophthalmology 111 (12), 2240e2245. Cheema, R.A., Peyman, G.A., Fang, T., Jones, A., Lukaris, A.D., Lim, K., 2007. Triamcinolone acetonide as an adjuvant in the surgical treatment of retinal detachment with proliferative vitreoretinopathy. Ophthalmic Surg. Laser Imag. Off. J. Int. Soc. Imaging Eye 38 (5), 365e370. Chovatiya, R., Medzhitov, R., 2014. Stress, inflammation, and defense of homeostasis. Mol. Cell 54 (2), 281e288. Chung, H.T., Choi, B.M., Kwon, Y.G., Kim, Y.M., 2008. Interactive relations between nitric oxide (NO) and carbon monoxide (CO): heme oxygenase-1/CO pathway is a key modulator in NO-mediated antiapoptosis and anti-inflammation. Methods Enzym. 441, 329e338. Claes, C., Lafeta, A.P., 2014. Proliferative vitreoretinopathy. Dev. Ophthalmol. 54, 188e195. Coffee, R.E., Jiang, L., Rahman, S.A., 2014. Proliferative vitreoretinopathy: advances in surgical management. Int. Ophthalmol. Clin. 54 (2), 91e109. Colak, D., Morales, J., Bosley, T.M., Al-Bakheet, A., AlYounes, B., Kaya, N., AbuAmero, K.K., 2012. Genome-wide expression profiling of patients with primary open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 53 (9), 5899e5904. Crawford, Y., Ferrara, N., 2009. Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies. Trends Pharmacol. Sci. 30 (12), 624e630. Crawford, Y., Kasman, I., Yu, L., Zhong, C., Wu, X., Modrusan, Z., Kaminker, J., Ferrara, N., 2009. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15 (1), 21e34. Cui, J., Lei, H., Samad, A., Basavanthappa, S., Maberley, D., Matsubara, J., Kazlauskas, A., 2009. PDGF receptors are activated in human epiretinal membranes. Exp. eye Res. 88 (3), 438e444. Curcio, C.A., Johnson, M., Rudolf, M., Huang, J.D., 2011. The oil spill in ageing Bruch membrane. Br. J. Ophthalmol. 95 (12), 1638e1645. Curcio, C.A., Presley, J.B., Millican, C.L., Medeiros, N.E., 2005. Basal deposits and drusen in eyes with age-related maculopathy: evidence for solid lipid particles. Exp. eye Res. 80 (6), 761e775. Dai, X., Okon, I., Liu, Z., Bedarida, T., Wang, Q., Ramprasath, T., Zhang, M., Song, P., Zou, M.H., 2017. Ablation of neuropilin 1 in myeloid cells exacerbates high-fat diet-induced insulin resistance through Nlrp3 inflammasome in vivo. Diabetes 66 (9), 2424e2435. Daiger, S.P., Bowne, S.J., Sullivan, L.S., 2007. Perspective on genes and mutations causing retinitis pigmentosa. Arch. Ophthalmol. 125 (2), 151e158. Dejda, A., Mawambo, G., Daudelin, J.F., Miloudi, K., Akla, N., Patel, C., Andriessen, E.M., Labrecque, N., Sennlaub, F., Sapieha, P., 2016. Neuropilin-1Expressing microglia are associated with nascent retinal vasculature yet dispensable for developmental angiogenesis. Invest. Ophthalmol. Vis. Sci. 57 (4), 1530e1536. Dong, A., Seidel, C., Snell, D., Ekawardhani, S., Ahlskog, J.K., Baumann, M., Shen, J., Iwase, T., Tian, J., Stevens, R., Hackett, S.F., Stumpp, M.T., Campochiaro, P.A., 2014. Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A. Angiogenesis 17 (3), 553e562. Doolittle, R.F., Hunkapiller, M.W., Hood, L.E., Devare, S.G., Robbins, K.C., Aaronson, S.A., Antoniades, H.N., 1983. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221 (4607), 275e277. Dunn, E.N., Hariprasad, S.M., Sheth, V.S., 2017. An overview of the Fovista and rinucumab trials and the fate of anti-PDGF medications. Ophthalmic Surg. Laser Imag. Retin. 48 (2), 100e104. Eichten, A., Su, J., Adler, A., Zhang, L., Ioffe, E., Parveen, A.A., Yancopoulos, G.D., Rudge, J.S., Lowy, I., Lin, C., MacDonald, D., Daly, C., Duan, X., Thurston, G., 2016. Resistance to anti-VEGF therapy mediated by autocrine IL-6/STAT3 signaling and overcome by IL-6 blockade. Cancer Res. 76 (8), 2327e2339. Feist Jr., R.M., King, J.L., Morris, R., Witherspoon, C.D., Guidry, C., 2014. Myofibroblast and extracellular matrix origins in proliferative vitreoretinopathy. Graefe's Arch. Clin. Exp. Ophthalmol. ¼ Albr. Graefes Arch. Klin. Exp. Ophthalmol. 252 (2), 347e357.

9

Ferrara, N., 2016. VEGF and intraocular neovascularization: from discovery to therapy. Transl. Vis. Sci. Technol. 5 (2), 10. Ferrari, S., Di Iorio, E., Barbaro, V., Ponzin, D., Sorrentino, F.S., Parmeggiani, F., 2011. Retinitis pigmentosa: genes and disease mechanisms. Curr. genomics 12 (4), 238e249. Ferris 3rd, F.L., Wilkinson, C.P., Bird, A., Chakravarthy, U., Chew, E., Csaky, K., Sadda, S.R., Beckman Initiative for Macular Research Classification, C., 2013. Clinical classification of age-related macular degeneration. Ophthalmology 120 (4), 844e851. Foster, P.J., Buhrmann, R., Quigley, H.A., Johnson, G.J., 2002. The definition and classification of glaucoma in prevalence surveys. Br. J. Ophthalmol. 86 (2), 238e242. Fredriksson, L., Li, H., Eriksson, U., 2004. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 15 (4), 197e204. Fritsche, L.G., Fariss, R.N., Stambolian, D., Abecasis, G.R., Curcio, C.A., Swaroop, A., 2014. Age-related macular degeneration: genetics and biology coming together. Annu. Rev. Genom. Hum. Genet. 15, 151e171. Gelfand, B.D., Ambati, J., 2016. A revised hemodynamic theory of age-related macular degeneration. Trends Mol. Med. 22 (8), 656e670. Gilbertson, D.G., Duff, M.E., West, J.W., Kelly, J.D., Sheppard, P.O., Hofstrand, P.D., Gao, Z., Shoemaker, K., Bukowski, T.R., Moore, M., Feldhaus, A.L., Humes, J.M., Palmer, T.E., Hart, C.E., 2001. Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. J. Biol. Chem. 276 (29), 27406e27414. Guerrero, A.H., Latina, M.A., 2000. Complications of glaucoma drainage implant surgery. Int. Ophthalmol. Clin. 40 (1), 149e163. Hamada, T., Ui-Tei, K., Imaki, J., Takahashi, F., Onodera, H., Mishima, T., Miyata, Y., 2002. The expression of SCDGF/PDGF-C/fallotein and SCDGF-B/PDGF-D in the rat central nervous system. Mech. Dev. 112 (1e2), 161e164. Hammond, C.J., Webster, A.R., Snieder, H., Bird, A.C., Gilbert, C.E., Spector, T.D., 2002. Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 109 (4), 730e736. Harada, C., Mitamura, Y., Harada, T., 2006. The role of cytokines and trophic factors in epiretinal membranes: involvement of signal transduction in glial cells. Prog. Retin. Eye Res. 25 (2), 149e164. Hartnett, M.E., 2003. Features associated with surgical outcome in patients with stages 4 and 5 retinopathy of prematurity. Retina 23 (3), 322e329. Hartnett, M.E., 2017. Role of cytokines and treatment algorithms in retinopathy of prematurity. Curr. Opin. Ophthalmol. 28 (3), 282e288. Hartnett, M.E., Weiter, J.J., Garsd, A., Jalkh, A.E., 1992. Classification of retinal pigment epithelial detachments associated with drusen. Graefe's Arch. Clin. Exp. Ophthalmol. ¼ Albr. Graefes Arch. Klin. Exp. Ophthalmol. 230 (1), 11e19. Hartong, D.T., Berson, E.L., Dryja, T.P., 2006. Retinitis pigmentosa. Lancet 368 (9549), 1795e1809. He, C., Zhao, C., Kumar, A., Lee, C., Chen, M., Huang, L., Wang, J., Ren, X., Jiang, Y., Chen, W., Wang, B., Gao, Z., Zhong, Z., Huang, Z., Zhang, F., Huang, B., Ding, H., Ju, R., Tang, Z., Liu, Y., Cao, Y., Li, X., Liu, X., 2014. Vasoprotective effect of PDGFCC mediated by HMOX1 rescues retinal degeneration. Proc. Natl. Acad. Sci. U. S. A. 111 (41), 14806e14811. Heldin, C.-H., Johnsson, A., Wennergren, S., Wernstedt, C., Betsholtz, C., Westermark, B., 1986. A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains. Nature 319 (6053), 511e514. Hou, H., Huffman, K., Rios, S., Freeman, W.R., Sailor, M.J., Cheng, L., 2015. A novel approach of daunorubicin application on formation of proliferative retinopathy using a porous silicon controlled delivery system: pharmacodynamics. Invest. Ophthalmol. Vis. Sci. 56 (4), 2755e2763. Hou, X., Kumar, A., Lee, C., Wang, B., Arjunan, P., Dong, L., Maminishkis, A., Tang, Z., Li, Y., Zhang, F., Zhang, S.Z., Wardega, P., Chakrabarty, S., Liu, B., Wu, Z., Colosi, P., Fariss, R.N., Lennartsson, J., Nussenblatt, R., Gutkind, J.S., Cao, Y., Li, X., 2010. PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets. Proc. Natl. Acad. Sci. U. S. A. 107 (27), 12216e12221. Jaffe, G.J., Ciulla, T.A., Ciardella, A.P., Devin, F., Dugel, P.U., Eandi, C.M., Masonson, H., Mones, J., Pearlman, J.A., Quaranta-El Maftouhi, M., Ricci, F., Westby, K., Patel, S.C., 2017. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology 124 (2), 224e234. Jaffe, G.J., Eliott, D., Wells, J.A., Prenner, J.L., Papp, A., Patel, S., 2016. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular agerelated macular degeneration. Ophthalmology 123 (1), 78e85. Ji, J.Z., Elyaman, W., Yip, H.K., Lee, V.W., Yick, L.W., Hugon, J., So, K.F., 2004. CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur. J. Neurosci. 19 (2), 265e272. Jin, E., Yin, H., Li, X., Zhao, M., 2017. Short-term outcomes after intravitreal injections of conbercept versus ranibizumab for the treatment of retinopathy of prematurity. Retina. Johnsson, A., Heldin, C.H., Westermark, B., Wasteson, A., 1982. Platelet-derived growth factor: identification of constituent polypeptide chains. Biochem. Biophys. Res. Commun. 104 (1), 66e74. Kanamoto, T., Rimayanti, U.,H.,O., Kiuchi, Y., 2011. Platelet-derived growth factor receptor alpha is associated with oxidative stress-induced retinal cell death. Curr. eye Res. 36 (4), 336e340. Kandasamy, Y., Hartley, L., Rudd, D., Smith, R., 2017. The association between

Please cite this article in press as: Kumar, A., Li, X., PDGF-C and PDGF-D in ocular diseases, Molecular Aspects of Medicine (2017), https://doi.org/ 10.1016/j.mam.2017.10.002

10

A. Kumar, X. Li / Molecular Aspects of Medicine xxx (2017) 1e11

systemic vascular endothelial growth factor and retinopathy of prematurity in premature infants: a systematic review. Br. J. Ophthalmol. 101 (1), 21e24. Kapetanakis, V.V., Chan, M.P., Foster, P.J., Cook, D.G., Owen, C.G., Rudnicka, A.R., 2016. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br. J. Ophthalmol. 100 (1), 86e93. Karvinen, H., Rutanen, J., Leppanen, O., Lach, R., Levonen, A.L., Eriksson, U., YlaHerttuala, S., 2009. PDGF-C and -D and their receptors PDGFR-alpha and PDGFR-beta in atherosclerotic human arteries. Eur. J. Clin. Invest. 39 (4), 320e327. Kazlauskas, A., 2017. PDGFs and their receptors. Gene 614, 1e7. Kingman, S., 2004. Glaucoma is second leading cause of blindness globally. Bull. World Health Organ. 82 (11), 887e888. Klein, R., Cruickshanks, K.J., Nash, S.D., Krantz, E.M., Nieto, F.J., Huang, G.H., Pankow, J.S., Klein, B.E., 2010. The prevalence of age-related macular degeneration and associated risk factors. Arch. Ophthalmol. 128 (6), 750e758. Klein, R., Klein, B.E., Linton, K.L., 1992. Prevalence of age-related maculopathy. The beaver dam eye study. Ophthalmology 99 (6), 933e943. Ko, M.L., Hu, D.N., Ritch, R., Sharma, S.C., Chen, C.F., 2001. Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci. Lett. 305 (2), 139e142. Kohler, N., Lipton, A., 1974. Platelets as a source of fibroblast growth-promoting activity. Exp. Cell Res. 87 (2), 297e301. Ku, C.A., Chiodo, V.A., Boye, S.L., Hayes, A., Goldberg, A.F., Hauswirth, W.W., Ramamurthy, V., 2015. Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model. Hum. Mol. Genet. 24 (3), 670e684. Kumar, A., Hou, X., Lee, C., Li, Y., Maminishkis, A., Tang, Z., Zhang, F., Langer, H.F., Arjunan, P., Dong, L., Wu, Z., Zhu, L.Y., Wang, L., Min, W., Colosi, P., Chavakis, T., Li, X., 2010. Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation. J. Biol. Chem. 285 (20), 15500e15510. Kumar, A., Zhao, L., Fariss, R.N., McMenamin, P.G., Wong, W.T., 2014. Vascular associations and dynamic process motility in perivascular myeloid cells of the mouse choroid: implications for function and senescent change. Invest. Ophthalmol. Vis. Sci. 55 (3), 1787e1796. LaRochelle, W.J., Jeffers, M., McDonald, W.F., Chillakuru, R.A., Giese, N.A., Lokker, N.A., Sullivan, C., Boldog, F.L., Yang, M., Vernet, C., Burgess, C.E., Fernandes, E., Deegler, L.L., Rittman, B., Shimkets, J., Shimkets, R.A., Rothberg, J.M., Lichenstein, H.S., 2001. PDGF-D, a new protease-activated growth factor. Nat. Cell Biol. 3 (5), 517e521. Lee, C., Zhang, F., Tang, Z., Liu, Y., Li, X., 2013. PDGF-C: a new performer in the neurovascular interplay. Trends Mol. Med. 19 (8), 474e486. Lei, H., Hovland, P., Velez, G., Haran, A., Gilbertson, D., Hirose, T., Kazlauskas, A., 2007. A potential role for PDGF-C in experimental and clinical proliferative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 48 (5), 2335e2342. Lei, H., Kazlauskas, A., 2008. Focus on molecules: platelet-derived growth factor C, PDGF-C. Exp. eye Res. 86 (5), 711e712. Lei, H., Kazlauskas, A., 2014. A reactive oxygen species-mediated, self-perpetuating loop persistently activates platelet-derived growth factor receptor alpha. Mol. Cell. Biol. 34 (1), 110e122. Lei, H., Velez, G., Hovland, P., Hirose, T., Kazlauskas, A., 2008. Plasmin is the major protease responsible for processing PDGF-C in the vitreous of patients with proliferative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 49 (1), 42e48. Lei, H., Velez, G., Kazlauskas, A., 2011. Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53. Mol. Cell. Biol. 31 (9), 1788e1799. Li, H., Wang, H., Wang, F., Gu, Q., Xu, X., 2011. Snail involves in the transforming growth factor beta1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells. PLoS One 6 (8), e23322. Li, R., Maminishkis, A., Wang, F.E., Miller, S.S., 2007. PDGF-C and -D induced proliferation/migration of human RPE is abolished by inflammatory cytokines. Invest. Ophthalmol. Vis. Sci. 48 (12), 5722e5732. Li, X., Eriksson, U., 2003. Novel PDGF family members: PDGF-C and PDGF-D. Cytokine & growth factor Rev. 14 (2), 91e98. Li, X., Kumar, A., Zhang, F., Lee, C., Li, Y., Tang, Z., Arjuna, P., 2010. VEGF-independent angiogenic pathways induced by PDGF-C. Oncotarget 1 (4), 309e314. Li, X., Ponten, A., Aase, K., Karlsson, L., Abramsson, A., Uutela, M., Backstrom, G., Hellstrom, M., Bostrom, H., Li, H., Soriano, P., Betsholtz, C., Heldin, C.H., Alitalo, K., Ostman, A., Eriksson, U., 2000. PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat. Cell Biol. 2 (5), 302e309. Liegl, R., Hellstrom, A., Smith, L.E., 2016. Retinopathy of prematurity: the need for prevention. Eye Brain 8, 91e102. Limb, G.A., Little, B.C., Meager, A., Ogilvie, J.A., Wolstencroft, R.A., Franks, W.A., Chignell, A.H., Dumonde, D.C., 1991. Cytokines in proliferative vitreoretinopathy. Eye 5 (Pt 6), 686e693. Liu, B., McNally, S., Kilpatrick, J.I., Jarvis, S.P., O'Brien, C.J., 2017. Aging and ocular tissue stiffness in glaucoma. Surv. Ophthalmol. Liu, H., Tang, J., Du, Y., Saadane, A., Tonade, D., Samuels, I., Veenstra, A., Palczewski, K., Kern, T.S., 2016. Photoreceptor cells influence retinal vascular degeneration in mouse models of retinal degeneration and diabetes. Invest. Ophthalmol. Vis. Sci. 57 (10), 4272e4281. Long, C.A., 1989. Cryotherapy: a new treatment for retinopathy of prematurity. Pediatr. Nurs. 15 (3), 269e272. Ma, W., Wong, W.T., 2016. Aging changes in retinal microglia and their relevance to age-related retinal disease. Adv. Exp. Med. Biol. 854, 73e78.

McNamara, J.A., Tasman, W., Brown, G.C., Federman, J.L., 1991. Laser photocoagulation for stage 3þ retinopathy of prematurity. Ophthalmology 98 (5), 576e580. Miao, H., Tao, Y., Li, X.X., 2012. Inflammatory cytokines in aqueous humor of patients with choroidal neovascularization. Mol. Vis. 18, 574e580. Miller, J.W., 2013. Age-related macular degeneration revisitedepiecing the puzzle: the LXIX Edward Jackson memorial lecture. Am. J. Ophthalmol. 155 (1), 1e35 e13. Miller, J.W., Le Couter, J., Strauss, E.C., Ferrara, N., 2013. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120 (1), 106e114. Moran, E.P., Wang, Z., Chen, J., Sapieha, P., Smith, L.E., Ma, J.X., 2016. Neurovascular cross talk in diabetic retinopathy: pathophysiological roles and therapeutic implications. American journal of physiology. Heart Circ. Physiol. 311 (3), H738eH749. Mori, K., Gehlbach, P., Ando, A., Dyer, G., Lipinsky, E., Chaudhry, A.G., Hackett, S.F., Campochiaro, P.A., 2002. Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy. Invest. Ophthalmol. Vis. Sci. 43 (6), 2001e2006. Mowat, F.M., Occelli, L.M., Bartoe, J.T., Gervais, K.J., Bruewer, A.R., Querubin, J., Dinculescu, A., Boye, S.L., Hauswirth, W.W., Petersen-Jones, S.M., 2017. Gene therapy in a large animal model of PDE6A-retinitis pigmentosa. Front. Neurosci. 11, 342. Muhl, L., Folestad, E.B., Gladh, H., Wang, Y., Moessinger, C., Jakobsson, L., Eriksson, U., 2017. Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-DPDGFRbeta signaling. J. Cell Sci. 130 (8), 1365e1378. Narayanan, R., Kuppermann, B.D., 2017. Hot topics in dry AMD. Curr. Pharm. Des. 23 (4), 542e546. Ng, E.W., Adamis, A.P., 2006. Anti-VEGF aptamer (pegaptanib) therapy for ocular vascular diseases. Ann. N. Y. Acad. Sci. 1082, 151e171. Ng, E.W., Shima, D.T., Calias, P., Cunningham Jr., E.T., Guyer, D.R., Adamis, A.P., 2006. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nature Rev. Drug Discov. 5 (2), 123e132. Ohira, S., Inoue, T., Iwao, K., Takahashi, E., Tanihara, H., 2016. Factors influencing aqueous proinflammatory cytokines and growth factors in uveitic glaucoma. PLoS One 11 (1), e0147080. Parmeggiani, F., Sato, G., De Nadai, K., Romano, M.R., Binotto, A., Costagliola, C., 2011. Clinical and rehabilitative management of retinitis pigmentosa: up-to-date. Curr. genomics 12 (4), 250e259. Pastor, J.C., Rojas, J., Pastor-Idoate, S., Di Lauro, S., Gonzalez-Buendia, L., DelgadoTirado, S., 2016. Proliferative vitreoretinopathy: a new concept of disease pathogenesis and practical consequences. Prog. Retin. eye Res. 51, 125e155. Patel, J.R., Ranjan, S.S., Wasserman, B.N., 2016. Antivascular endothelial growth factor in the treatment of retinopathy of prematurity. Curr. Opin. Ophthalmol. 27 (5), 387e392. Peng, F., Yao, H., Akturk, H.K., Buch, S., 2012. Platelet-derived growth factor CCmediated neuroprotection against HIV Tat involves TRPC-mediated inactivation of GSK 3beta. PLoS One 7 (10), e47572. Peng, Y., Zhang, X., Mi, L., Liu, B., Zuo, C., Li, M., Wen, F., 2017. Efficacy and safety of conbercept as a primary treatment for choroidal neovascularization secondary to punctate inner choroidopathy. BMC Ophthalmol. 17 (1), 87. Pennock, S., Haddock, L.J., Eliott, D., Mukai, S., Kazlauskas, A., 2014. Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy? Prog. Retin. Eye Res. 40, 16e34. Pennock, S., Rheaume, M.A., Mukai, S., Kazlauskas, A., 2011. A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy. Am. J. Pathol. 179 (6), 2931e2940. Ponten, A., Folestad, E.B., Pietras, K., Eriksson, U., 2005. Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ. Res. 97 (10), 1036e1045. Powers, M.R., Davies, M.H., Eubanks, J.P., 2005. Increased expression of chemokine KC, an interleukin-8 homologue, in a model of oxygen-induced retinopathy. Curr. eye Res. 30 (4), 299e307. Quigley, H.A., 1996. Number of people with glaucoma worldwide. Br. J. Ophthalmol. 80 (5), 389e393. Ray, S., Gao, C., Wyatt, K., Fariss, R.N., Bundek, A., Zelenka, P., Wistow, G., 2005. Platelet-derived growth factor D, tissue-specific expression in the eye, and a key role in control of lens epithelial cell proliferation. J. Biol. Chem. 280 (9), 8494e8502. Reigstad, L.J., Varhaug, J.E., Lillehaug, J.R., 2005. Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family. FEBS J. 272 (22), 5723e5741. Rivera, J.C., Holm, M., Austeng, D., Morken, T.S., Zhou, T.E., Beaudry-Richard, A., Sierra, E.M., Dammann, O., Chemtob, S., 2017. Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies. J. Neuroinflammation 14 (1), 165. Robbins, S.G., Mixon, R.N., Wilson, D.J., Hart, C.E., Robertson, J.E., Westra, I., Planck, S.R., Rosenbaum, J.T., 1994. Platelet-derived growth factor ligands and receptors immunolocalized in proliferative retinal diseases. Invest. Ophthalmol. Vis. Sci. 35 (10), 3649e3663. Rosenfeld, P.J., Brown, D.M., Heier, J.S., Boyer, D.S., Kaiser, P.K., Chung, C.Y., Kim, R.Y., Group, M.S., 2006. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355 (14), 1419e1431. Rosenquist, R., Epstein, D., Melamed, S., Johnson, M., Grant, W.M., 1989. Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr. eye Res. 8 (12), 1233e1240. Rudnicka, A.R., Kapetanakis, V.V., Jarrar, Z., Wathern, A.K., Wormald, R.,

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A. Kumar, X. Li / Molecular Aspects of Medicine xxx (2017) 1e11 Fletcher, A.E., Cook, D.G., Owen, C.G., 2015. Incidence of late-stage age-related macular degeneration in american whites: systematic review and meta-analysis. Am. J. Ophthalmol. 160 (1), 85e93 e83. Rutar, M., Provis, J.M., 2016. Role of chemokines in shaping macrophage activity in AMD. Adv. Exp. Med. Biol. 854, 11e16. Sadaka, A., Giuliari, G.P., 2012. Proliferative vitreoretinopathy: current and emerging treatments. Clin. Ophthalmol. 6, 1325e1333. Sankar, M.J., Sankar, J., Mehta, M., Bhat, V., Srinivasan, R., 2016. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane database Syst. Rev. 2, CD009734. Sato, T., Kusaka, S., Shimojo, H., Fujikado, T., 2009. Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity. Ophthalmology 116 (11), 2165e2169. Savikko, J., von Willebrand, E., 2001. Coexpression of platelet-derived growth factors AA and BB and their receptors during monocytic differentiation. Transplant. Proc. 33 (3), 2307e2308. Seifert, R.A., Schwartz, S.M., Bowen-Pope, D.F., 1984. Developmentally regulated production of platelet-derived growth factor-like molecules. Nature 311 (5987), 669e671. Si, Y., Wang, J., Guan, J., Han, Q., Hui, Y., 2013. Platelet-derived growth factor induced alpha-smooth muscle actin expression by human retinal pigment epithelium cell. J. Ocul. Pharmacol. Ther. Off. J. Assoc. Ocul. Pharmacol. Ther. 29 (3), 310e318. Smith, C.L., Baek, S.T., Sung, C.Y., Tallquist, M.D., 2011. Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ. Res. 108 (12), e15e26. Smith, L.E., 2004. Pathogenesis of retinopathy of prematurity. Growth Horm. IGF Res. Off. J. Growth Horm. Res. Soc. Int. GF Res. Soc. 14 (Suppl. A), S140eS144. Smith, L.E., Wesolowski, E., McLellan, A., Kostyk, S.K., D'Amato, R., Sullivan, R., D'Amore, P.A., 1994. Oxygen-induced retinopathy in the mouse. Invest. Ophthalmol. Vis. Sci. 35 (1), 101e111. Sobrin, L., Seddon, J.M., 2014. Nature and nurture- genes and environment- predict onset and progression of macular degeneration. Prog. Retin. eye Res. 40, 1e15. Son, D., Na, Y.R., Hwang, E.S., Seok, S.H., 2014. Platelet-derived growth factor-C (PDGF-C) induces anti-apoptotic effects on macrophages through Akt and Bad phosphorylation. J. Biol. Chem. 289 (9), 6225e6235. study, G., 1986. Argon laser photocoagulation for neovascular maculopathy. Threeyear results from randomized clinical trials. Macular Photocoagulation Study Group. Arch. Ophthalmol. 104 (5), 694e701. Sundberg, C., Ljungstrom, M., Lindmark, G., Gerdin, B., Rubin, K., 1993. Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. Am. J. Pathol. 143 (5), 1377e1388. Sunness, J.S., Gonzalez-Baron, J., Bressler, N.M., Hawkins, B., Applegate, C.A., 1999. The development of choroidal neovascularization in eyes with the geographic atrophy form of age-related macular degeneration. Ophthalmology 106 (5), 910e919. Takahama, S., Adetunji, M.O., Zhao, T., Chen, S., Li, W., Tomarev, S.I., 2017. Retinal astrocytes and GABAergic wide-field amacrine cells express PDGFRalpha: connection to retinal ganglion cell neuroprotection by PDGF-AA. Invest. Ophthalmol. Vis. Sci. 58 (11), 4703e4711. Tang, Z., Arjunan, P., Lee, C., Li, Y., Kumar, A., Hou, X., Wang, B., Wardega, P., Zhang, F., Dong, L., Zhang, Y., Zhang, S.Z., Ding, H., Fariss, R.N., Becker, K.G., Lennartsson, J., Nagai, N., Cao, Y., Li, X., 2010. Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation. J. Exp. Med. 207 (4), 867e880. Tolentino, M.J., 2009. Current molecular understanding and future treatment strategies for pathologic ocular neovascularization. Curr. Mol. Med. 9 (8),

11

973e981. Uutela, M., Wirzenius, M., Paavonen, K., Rajantie, I., He, Y., Karpanen, T., Lohela, M., Wiig, H., Salven, P., Pajusola, K., Eriksson, U., Alitalo, K., 2004. PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood 104 (10), 3198e3204. Venugopalan, P., Wang, Y., Nguyen, T., Huang, A., Muller, K.J., Goldberg, J.L., 2016. Transplanted neurons integrate into adult retinas and respond to light. Nat. Commun. 7, 10472. Villegas, V.M., Aranguren, L.A., Kovach, J.L., Schwartz, S.G., Flynn Jr., H.W., 2017. Current advances in the treatment of neovascular age-related macular degeneration. Expert Opin. Drug Deliv. 14 (2), 273e282. Vinores, S.A., Henderer, J.D., Mahlow, J., Chiu, C., Derevjanik, N.L., Larochelle, W., Csaky, C., Campochiaro, P.A., 1995. Isoforms of platelet-derived growth factor and its receptors in epiretinal membranes: immunolocalization to retinal pigmented epithelial cells. Exp. eye Res. 60 (6), 607e619. Wagsater, D., Zhu, C., Bjorck, H.M., Eriksson, P., 2009. Effects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression. Atherosclerosis 202 (2), 415e423. Wang, L., Clark, M.E., Crossman, D.K., Kojima, K., Messinger, J.D., Mobley, J.A., Curcio, C.A., 2010. Abundant lipid and protein components of drusen. PLoS One 5 (4), e10329. Wegiel, B., Nemeth, Z., Correa-Costa, M., Bulmer, A.C., Otterbein, L.E., 2014. Heme oxygenase-1: a metabolic nike. Antioxidants Redox Signal. 20 (11), 1709e1722. Westermark, B., Wasteson, A., 1976. A platelet factor stimulating human normal glial cells. Exp. Cell Res. 98 (1), 170e174. Wilkinson-Berka, J.L., Babic, S., De Gooyer, T., Stitt, A.W., Jaworski, K., Ong, L.G., Kelly, D.J., Gilbert, R.E., 2004. Inhibition of platelet-derived growth factor promotes pericyte loss and angiogenesis in ischemic retinopathy. Am. J. Pathol. 164 (4), 1263e1273. Wilson, A.M., Di Polo, A., 2012. Gene therapy for retinal ganglion cell neuroprotection in glaucoma. Gene Ther. 19 (2), 127e136. Wiradjaja, F., Cottle, D.L., Jones, L., Smyth, I., 2013. Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice. Dis. Model. Mech. 6 (6), 1426e1433. Witmer, A.N., Vrensen, G.F., Van Noorden, C.J., Schlingemann, R.O., 2003. Vascular endothelial growth factors and angiogenesis in eye disease. Prog. Retin. Eye Res. 22 (1), 1e29. Wong, W.L., Su, X., Li, X., Cheung, C.M., Klein, R., Cheng, C.Y., Wong, T.Y., 2014. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet. Glob. Health 2 (2), e106e116. Wubben, T.J., Besirli, C.G., Zacks, D.N., 2016. Pharmacotherapies for retinal detachment. Ophthalmology 123 (7), 1553e1562. Xu, Y., Rong, A., Xu, W., Niu, Y., Wang, Z., 2017. Comparison of 12-month therapeutic effect of conbercept and ranibizumab for diabetic macular edema: a real-life clinical practice study. BMC Ophthalmol. 17 (1), 158. Yang, J., Liu, X., Nyland, S.B., Zhang, R., Ryland, L.K., Broeg, K., Baab, K.T., Jarbadan, N.R., Irby, R., Loughran Jr., T.P., 2010. Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. Blood 115 (1), 51e60. Yang, L., Lin, C., Liu, Z.R., 2006. P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell 127 (1), 139e155. Zeng, H.Y., Green, W.R., Tso, M.O., 2008. Microglial activation in human diabetic retinopathy. Arch. Ophthalmol. 126 (2), 227e232. Zin, A., Gole, G.A., 2013. Retinopathy of prematurity-incidence today. Clin. Perinatol. 40 (2), 185e200.

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