TY - JOUR
T1 - Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3β phosphorylation
AU - Kumar, Anil
AU - Hou, Xu
AU - Lee, Chunsik
AU - Li, Yang
AU - Maminishkis, Arvydas
AU - Tang, Zhongshu
AU - Zhang, Fan
AU - Langer, Harald F.
AU - Arjunan, Pachiappan
AU - Dong, Lijin
AU - Wu, Zhijian
AU - Zhu, Linda Y.
AU - Wang, Lianchun
AU - Min, Wang
AU - Colosi, Peter
AU - Chavakis, Triantafyllos
AU - Li, Xuri
PY - 2010/5/14
Y1 - 2010/5/14
N2 - 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-3β (GSK3β) Ser9 phosphorylation and Tyr216 dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3β activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3β 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.
AB - 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-3β (GSK3β) Ser9 phosphorylation and Tyr216 dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3β activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3β 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.
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U2 - 10.1074/jbc.M110.113787
DO - 10.1074/jbc.M110.113787
M3 - Article
C2 - 20231273
AN - SCOPUS:77952056907
SN - 0021-9258
VL - 285
SP - 15500
EP - 15510
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -