We investigated the role of PDGF-C and PDGF-D in ocular angiogenesis using two mouse models of ocular neovascularization, the laser-induced choroidal neovascularization (CNV) model and the retinopathy of prematurity (ROP) model. We found that PDGF-C and PDGF-D expression levels were markedly upregulated in the CNV and ROP models. Importantly, PDGF-C or PDGF-D inhibition by neutralizing antibody, shRNA or genetic deletion suppressed choroidal and retinal neovascularization. We further revealed that PDGF-C/D targeting acted on multiple cell types important for pathological angiogenesis, i.e., vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells. In addition, PDGF-C/D also regulated the expression of many important angiogenic genes. Mechanistically, we found that PDGF-C/D regulated glycogen synthase kinase (GSK)-3 phosphorylation and expression in ocular cells and tissues both in vitro and in vivo. Thus, we identified PDGF-C and PDGF-D as pleiotropic, versatile and important potential candidate target genes for antiangiogenic therapy. In collaboration with other NIH investigators, we studied the vascular effects of some other important molecules. We found that synthetic polyriboguanosine (poly G) and oligo-deoxyriboguanosine (oligo G) reduced neuropilin-1 expression in endothelial cells (ECs) and inhibited their angiogenic activities in vitro, and reduced choroidal neovascularization in mice in vivo. Moreover, we reported that semaphorin 3E initiated the antiangiogenic signaling through plexin-D. Activation of Plexin-D by Sema3E led to a rapid disassembly of adhesive structures in ECs, thereby causing the retraction of filopodia in endothelial tip cells in vitro and in vivo. In addition, we found that complement C3 and C5aR null mice displayed increased neovascularization in a retinopathy of prematurity mouse model, and macrophages mediated the antiangiogenic activity of complement. In the future, we plan to further our studies on the vascular and neuroprotective effects of VEGF-B, PDGF-C and PDGF-D using other ocular disease models. We will also study the vascular and neural effect of other important molecules expressed in the retina. Moreover, we will investigate the molecular mechanisms underlying the effects of the molecules of interest. Our work on several angiogenic and neuroprotective molecules has provided evidence of their potential therapeutic implications in treating neovascular and neurodegenerative diseases. Further studies are warranted to explore their translational potential. (1). PDGF/VEGF targeting in treating ocular neovascular diseases. Neovascular complication in the eye is the major cause of blindness in the old population and the Western society. Many angiogenesis inhibitors have been tested for treating such diseases, and beneficial effects have been demonstrated. Yet, the progression of such pathologies cannot be halted or reversed. Studies characterizing new molecules playing important roles in ocular neovascularization are therefore awaited. Ongoing work in our unit is investigating the angiogenic activity of the PDGFs/VEGFs in ocular neovascularization and the potential of PDGF/VEGF targeting in treating ocular vascular diseases. (2). Neuroprotection by growth factors in retinal neurodegenerative diseases. Neurodegeneration occurs in many types of ocular diseases. Numerous factors contribute to such diseases and there is currently no general treatment effective for all forms of retinal degeneration. Neuroprotection as achieved by neurotrophic/survival factors has emerged to be one general strategy for the treatment of such pathologies. However, the number of such neuroprotective factors is still limited. We are currently using multiple approaches including protein delivery, gene and cell therapy, normal and transgenic mice, in combination with other loss-of-function studies to investigate the neuroprotective effect of several growth factors in treating retinal neurodegenerative diseases.
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