PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

Xu Hou, Anil Kumar, Chunsik Lee, Bin Wang, Pachiappan Arjunan, Lijin Dong, Arvydas Maminishkis, Zhongshu Tang, Yang Li, Fan Zhang, Shi Zhuang Zhang, Piotr Wardega, Sagarika Chakrabarty, Baoying Liu, Zhijian Wu, Peter Colosi, Robert N. Fariss, Johan Lennartsson, Robert Nussenblatt, J. Silvio GutkindYihai Cao, Xuri Li

Research output: Contribution to journalArticle

56 Citations (Scopus)

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, 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.

Original languageEnglish (US)
Pages (from-to)12216-12221
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number27
DOIs
StatePublished - Jul 6 2010
Externally publishedYes

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Pathologic Neovascularization
Vascular Endothelial Growth Factor A
Retinal Neovascularization
Glycogen Synthase Kinase 3
platelet-derived growth factor C
Platelet-Derived Growth Factor Receptors
Choroidal Neovascularization
Retinal Pigments
Neutralizing Antibodies
Drug Resistance
Genetic Therapy
Small Interfering RNA
Endothelial Cells
Animal Models
Epithelial Cells
Macrophages
Phosphorylation

Keywords

  • Choroidal neovascularization
  • Glycogen synthase kinase-3β
  • Ocular disease
  • Retinal neovascularization
  • Vascular biology

ASJC Scopus subject areas

  • General

Cite this

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets. / Hou, Xu; Kumar, Anil; Lee, Chunsik; Wang, Bin; Arjunan, Pachiappan; Dong, Lijin; Maminishkis, Arvydas; Tang, Zhongshu; Li, Yang; Zhang, Fan; Zhang, Shi Zhuang; Wardega, Piotr; Chakrabarty, Sagarika; Liu, Baoying; Wu, Zhijian; Colosi, Peter; Fariss, Robert N.; Lennartsson, Johan; Nussenblatt, Robert; Gutkind, J. Silvio; Cao, Yihai; Li, Xuri.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 27, 06.07.2010, p. 12216-12221.

Research output: Contribution to journalArticle

Hou, X, Kumar, A, Lee, C, Wang, B, Arjunan, P, Dong, L, Maminishkis, A, Tang, Z, Li, Y, Zhang, F, Zhang, SZ, Wardega, P, Chakrabarty, S, Liu, B, Wu, Z, Colosi, P, Fariss, RN, Lennartsson, J, Nussenblatt, R, Gutkind, JS, Cao, Y & Li, X 2010, 'PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 27, pp. 12216-12221. https://doi.org/10.1073/pnas.1004143107
Hou, Xu ; Kumar, Anil ; Lee, Chunsik ; Wang, Bin ; Arjunan, Pachiappan ; Dong, Lijin ; Maminishkis, Arvydas ; Tang, Zhongshu ; Li, Yang ; Zhang, Fan ; Zhang, Shi Zhuang ; Wardega, Piotr ; Chakrabarty, Sagarika ; Liu, Baoying ; Wu, Zhijian ; Colosi, Peter ; Fariss, Robert N. ; Lennartsson, Johan ; Nussenblatt, Robert ; Gutkind, J. Silvio ; Cao, Yihai ; Li, Xuri. / PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 27. pp. 12216-12221.
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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, 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.",
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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

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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

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