VEGF plays an important role in both physiological revascularization and neovascularization in animal models of ROP.
67 Although anti-VEGF therapy is effective in preventing and reversing neovascularization, it also inhibits physiological revascularization,
6,68 a major limitation to its clinical use. Recent identification of additional factors involved in pathologic vascular growth
69,70 will be beneficial to the development of new therapeutics of ROP and other ischemic eye diseases with better selectivity toward pathologic neovascularization.
10,71–73 As shown in
Figures 1 to
3, pNaKtide treatment blocks retinal endothelial cell proliferation in vitro and limits neovascularization, as observed with anti-VEGF approaches.
6,74 However, unlike anti-VEGF, physiological revascularization does occur in pNaKtide-treated retinas, suggesting that the specific control of NKAL is more akin to target pathological vessel growth while preserving physiologically appropriate levels of ROS (generated in restricted amounts or in a transient fashion
75), VEGF, and other biological mediators that are essential for physiological angiogenesis in vivo. Although the biology of vascular endothelial cells is central to both physiological revascularization and neovascularization, it is also well known that other cell types (e.g., neurons, glia cells, or macrophages) expressing the ubiquitous α1 NKA are involved in the pathogenesis of ROP.
76–78 Thus, in addition to the role of α1 NKA signaling in vascular endothelial cells,
79 additional studies are needed to explore cell-specific roles of α1 NKA in ROP and other ischemic retinopathies. Among the most compelling non-endothelial mechanisms to be considered, the regulation of inflammatory cytokines by α1 NKA signaling in macrophages is one that deserves high priority and attention.
80 It is also noted that, although the mouse model is widely used to study OIR,
81 it differs from ROP in some of its clinical manifestations. Hence, neovascularization spontaneously regresses in the mouse model between P17 and P24,
42 whereas in human preterm infants with severe ROP the condition worsens. Second, the vaso-obliteration observed in the OIR mouse model is primarily due to constant exposure to hyperoxia, whereas the pattern of obliteration in human ROP (central vessels rather than peripheral vessels in the mouse ROI model) results from intermittent hypoxemic and hyperoxic episodes due to immature neuronal network.
82,83