TY - JOUR
T1 - PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets
AU - Hou, Xu
AU - Kumar, Anil
AU - Lee, Chunsik
AU - Wang, Bin
AU - Arjunan, Pachiappan
AU - Dong, Lijin
AU - Maminishkis, Arvydas
AU - Tang, Zhongshu
AU - Li, Yang
AU - Zhang, Fan
AU - Zhang, Shi Zhuang
AU - Wardega, Piotr
AU - Chakrabarty, Sagarika
AU - Liu, Baoying
AU - Wu, Zhijian
AU - Colosi, Peter
AU - Fariss, Robert N.
AU - Lennartsson, Johan
AU - Nussenblatt, Robert
AU - Gutkind, J. Silvio
AU - Cao, Yihai
AU - Li, Xuri
PY - 2010/7/6
Y1 - 2010/7/6
N2 - 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, choroidalfibroblasts 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)-3β phosphorylation and expression both in vitro and in vivo. Activation of GSK3β impaired PDGF-CC-induced angiogenesis, and inhibition of GSK3β 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.
AB - 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, choroidalfibroblasts 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)-3β phosphorylation and expression both in vitro and in vivo. Activation of GSK3β impaired PDGF-CC-induced angiogenesis, and inhibition of GSK3β 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.
KW - Choroidal neovascularization
KW - Glycogen synthase kinase-3β
KW - Ocular disease
KW - Retinal neovascularization
KW - Vascular biology
UR - http://www.scopus.com/inward/record.url?scp=77955435616&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955435616&partnerID=8YFLogxK
U2 - 10.1073/pnas.1004143107
DO - 10.1073/pnas.1004143107
M3 - Article
C2 - 20566880
AN - SCOPUS:77955435616
SN - 0027-8424
VL - 107
SP - 12216
EP - 12221
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -