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 journalArticlepeer-review

61 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • General

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