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

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, choroidal fibroblasts 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)-3beta phosphorylation and expression both in vitro and in vivo. Activation of GSK3beta impaired PDGF-CC-induced angiogenesis, and inhibition of GSK3beta 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.

• Authors: 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 Gutkind, Yihai Cao, Xuri Li
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 27 Pg. 12216-21 (Jul 06 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20566880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Lymphokines
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• platelet-derived growth factor C
• Becaplermin
• Receptors, Platelet-Derived Growth Factor
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Animals
• Antibodies, Neutralizing (pharmacology)
• Becaplermin
• Blotting, Western
• Cells, Cultured
• Chick Embryo
• Choroidal Neovascularization (genetics, metabolism, prevention & control)
• Female
• Fluorescent Antibody Technique
• Gene Expression Regulation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Lymphokines (genetics, immunology, metabolism)
• Macrophages (cytology, drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic (genetics, metabolism, prevention & control)
• Phosphorylation
• Platelet-Derived Growth Factor (genetics, immunology, metabolism)
• Proto-Oncogene Proteins c-sis
• RNA Interference
• Receptors, Platelet-Derived Growth Factor (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction