title: PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets.
abstract: The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of the emerging drug resistance to anti-VEGF therapies. PDGF-CC is the third member of the PDGF family discovered after more than two decades of studies on PDGF-AA and PDGF-BB. The biological function of PDGF-CC and the underlying cellular and molecular mechanisms remain largely unexplored. Here, using different animal models, we report that PDGF-CC inhibition by neutralizing antibody, shRNA, or genetic deletion suppressed both choroidal and retinal neovascularization. Importantly, we revealed that PDGF-CC targeting acted not only on multiple cell types important for pathological angiogenesis, such as vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells, but also on the expression of other important angiogenic genes, such as PDGF-BB and PDGF receptors. At a molecular level, we found that PDGF-CC regulated glycogen synthase kinase (GSK)-3beta phosphorylation and expression both in vitro and in vivo. Activation of GSK3beta impaired PDGF-CC-induced angiogenesis, and inhibition of GSK3beta abolished the antiangiogenic effect of PDGF-CC blockade. Thus, we identified PDGF-CC as an important candidate target gene for antiangiogenic therapy, and PDGF-CC inhibition may be of therapeutic value in treating neovascular diseases.
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Hou
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Chunsik
authors.initials: C
authors.lastname: Lee
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Pachiappan
authors.initials: P
authors.lastname: Arjunan
authors.forename: Lijin
authors.initials: L
authors.lastname: Dong
authors.forename: Arvydas
authors.initials: A
authors.lastname: Maminishkis
authors.forename: Zhongshu
authors.initials: Z
authors.lastname: Tang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Shi-Zhuang
authors.initials: SZ
authors.lastname: Zhang
authors.forename: Piotr
authors.initials: P
authors.lastname: Wardega
authors.forename: Sagarika
authors.initials: S
authors.lastname: Chakrabarty
authors.forename: Baoying
authors.initials: B
authors.lastname: Liu
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
authors.forename: Peter
authors.initials: P
authors.lastname: Colosi
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
authors.forename: Johan
authors.initials: J
authors.lastname: Lennartsson
authors.forename: Robert
authors.initials: R
authors.lastname: Nussenblatt
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.forename: Xuri
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000077214:Becaplermin; D015153:Blotting, Western; D002478:Cells, Cultured; D002642:Chick Embryo; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008222:Lymphokines / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034622:RNA Interference; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D057134:Antibodies, Neutralizing; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C411423:platelet-derived growth factor C; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3