br Conflict s of interest br Retinopathy of

Conflict(s) of interest
Retinopathy of prematurity (ROP) is a leading cause of childhood blindness Retinopathy of prematurity (ROP) is a disease of premature infants which disrupts normal retinal vascularization (Fleck and McIntosh, 2008). With increased survival of extremely premature infants due to advances in neonatology, ROP has become a major cause of childhood blindness (50,000–100,000 cases/year) in many parts of the world (Fleck and McIntosh, 2008, Gilbert, 2008). ROP is caused by oxygen-induced damage to the developing retinal vasculature (Gilbert, 2008, Chen et al., 2008, Dhaliwal et al., 2009) and is characterized by the hyperoxia-induced vaso-obliteration, subsequent delayed retinal vascularization, and hypoxia-induced pathological neovascularization (Fleck and McIntosh, 2008, Cavallaro et al., 2014) driven by hypoxia-induced factor-1α (HIF-1α) signaling pathway and increased vascular endothelial growth factor (VEGF) levels in retina (Cavallaro et al., 2014, Penn et al., 2008) (see Fig. 1A). Characteristic pathological changes include vaso-obliteration and proliferation of abnormal fibrovascular tissue at the border of the vascularised and non-vascularised retina (Fleck and McIntosh, 2008). Conventional therapies for ROP are limited to laser to ablate the avascular retina to prevent retinal detachment caused by ROP (Clark and Mandal, 2008), but the efficacy of ablative laser therapy are limited, and are associated with destruction to retina causing clinically significant loss of visual field. Anti-VEGF therapy (e.g. intra-vitreal injection of anti-VEGF-A antibody bevacizumab) was also proposed (Clark and Mandal, 2008) and has been recently shown to be effective in a randomized, controlled trial (Mintz-Hittner et al., 2011). However, the long term effect of intra-vitreal bevacizumab remains unclear with reported persistent avascular retina (Tokunaga et al., 2014) and recurrent intra-vitreal neovascularization (Hu et al., 2012). Importantly, VEGF acts as an angiogenic and a neurotrophic factor for normal retinal neural and vascular development (Tokunaga et al., 2014, Robinson et al., 2001, McCloskey et al., 2013). There are concerns on the unintended effects of anti-VEGF agents on delayed eye growth and retinal vasculature development of preterm infants who are still forming new blood vessels in many different mdm2 inhibitor (Nishijima et al., 2007, Saint-Geniez et al., 2008). Thus, there is a critical need to develop more effective and preferably non-invasive prophylactic and therapeutic strategies for ROP.
Normal retinal vascular development and pathological angiogenesis in ROP An ideal therapeutic strategy for ROP is to selectively control pathological neovascularization/angiogenesis without affecting normal retinal vasculature during postnatal development. The key to this strategy is to distinguish pathological angiogenesis process from normal retinal vascular development. Normal retinal vascular development starts with the de novo formation of blood vessels from endothelial precursor cells (vasculogenesis) (Lutty and McLeod, 2003, Gariano, 2003). This is followed by development of new blood vessels by budding from existing blood vessels (angiogenesis) (Gariano, 2003). A critical event in the pathogenesis of ROP is oxygen-induced damage to the developing retinal vasculature. ROP occurs in two distinct phases: first, the developing retina is exposed to a relatively hyperoxic environment, which damages developing retinal vessels, (Aiello et al., 1994, Alon et al., 1995). Consequently, retinal vascularization is delayed, resulting in vaso-obliteration. Second, as the avascular retina becomes critically hypoxic, increased VEGF production leads to physiological revascularization of the central retina and pathological angiogenesis with formation of preretinal vascular tufts (Fleck and McIntosh, 2008, Lutty and McLeod, 2003), ultimately resulting in traction retinal detachment and blindness. Oxygen-induced retinopathy (OIR) is an animal model of ROP that recapitulates some characteristic pathophysiological features of ROP, including vaso-obliteration, physiological revascularization and pathological angiogenesis (Fleck and McIntosh, 2008, Aiello et al., 1994, Alon et al., 1995). Normal vascular development and pathological angiogenesis share some common pathways: HIF-1α and angiogenic factors such as VEGF are involved in both processes (Lutty and McLeod, 2003, Gariano, 2003). Distinct molecular and morphological processes have been documented for those processes. While developmental and physiological vascularization is a highly organized process, producing distinct superficial and deep vasculature plexuses in retina (Gariano, 2003), pathological angiogenesis generates new vessels in the preretinal area that are unorganized and leaky, with a tortuous architecture (Gariano, 2003, Powers et al., 2008). Furthermore, distinct cellular mechanisms may also underlie these two processes. For instance, astrocytes play an important role in normal development of retinal vasculatures by forming a template that provides guidance for the developing vascular network (Stone et al., 1995, Stone et al., 1996). However, VEGF released from astrocytes reactive to hypoxia is critical for pathological angiogenesis in the retina following OIR but not essential to developmental angiogenesis (Weidemann et al., ; Dorrell et al.,). Furthermore, a recent study indicates that deletion of bone marrow derived cells by transplantation may preferentially affect developmental angiogenesis than pathological angiogenesis (Zou et al.,). These distinct characteristics provide a biological basis for selectively targeting pathological angiogenesis without affecting normal postnatal vascular development.