Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.
Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Anil
A
Kumar
NEI, National Institutes of Health, Bethesda, Maryland 20852; Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
Xu
X
Hou
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Chunsik
C
Lee
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Yang
Y
Li
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Arvydas
A
Maminishkis
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Zhongshu
Z
Tang
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Fan
F
Zhang
Experimental Immunology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892; Department of Cardiovascular Medicine, University of Tuebingen, 72076 Tuebingen, Germany.
Harald F
HF
Langer
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Pachiappan
P
Arjunan
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Lijin
L
Dong
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Zhijian
Z
Wu
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Linda Y
LY
Zhu
Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
Lianchun
L
Wang
Department of Pathology, Vascular Biology, and Therapeutics, Yale University, New Haven, Connecticut 06520.
Wang
W
Min
NEI, National Institutes of Health, Bethesda, Maryland 20852.
Peter
P
Colosi
Experimental Immunology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
Triantafyllos
T
Chavakis
NEI, National Institutes of Health, Bethesda, Maryland 20852. Electronic address: lixur@nei.nih.gov.
Xuri
X
Li
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012171:Retinal Vessels / Q000473:pathology; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D008222:Lymphokines; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor; D014443:Tyrosine; D012694:Serine; D020797:Receptor, Platelet-Derived Growth Factor beta; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3