Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3β phosphorylation

Anil Kumar, Xu Hou, Chunsik Lee, Yang Li, Arvydas Maminishkis, Zhongshu Tang, Fan Zhang, Harald F. Langer, Pachiappan Arjunan, Lijin Dong, Zhijian Wu, Linda Y. Zhu, Lianchun Wang, Wang Min, Peter Colosi, Triantafyllos Chavakis, Xuri Li

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)15500-15510
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number20
DOIs
StatePublished - May 14 2010

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Pathologic Neovascularization
Glycogen Synthase Kinase 3
Phosphorylation
Platelet-Derived Growth Factor
Genes
Retinal Neovascularization
Choroidal Neovascularization
Genetic Therapy
Blood Vessels
Cell Survival
Animals
Animal Models
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3β phosphorylation. / Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F.; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y.; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri.

In: Journal of Biological Chemistry, Vol. 285, No. 20, 14.05.2010, p. 15500-15510.

Research output: Contribution to journalArticle

Kumar, A, Hou, X, Lee, C, Li, Y, Maminishkis, A, Tang, Z, Zhang, F, Langer, HF, Arjunan, P, Dong, L, Wu, Z, Zhu, LY, Wang, L, Min, W, Colosi, P, Chavakis, T & Li, X 2010, 'Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3β phosphorylation', Journal of Biological Chemistry, vol. 285, no. 20, pp. 15500-15510. https://doi.org/10.1074/jbc.M110.113787
Kumar, Anil ; Hou, Xu ; Lee, Chunsik ; Li, Yang ; Maminishkis, Arvydas ; Tang, Zhongshu ; Zhang, Fan ; Langer, Harald F. ; Arjunan, Pachiappan ; Dong, Lijin ; Wu, Zhijian ; Zhu, Linda Y. ; Wang, Lianchun ; Min, Wang ; Colosi, Peter ; Chavakis, Triantafyllos ; Li, Xuri. / Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3β phosphorylation. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 20. pp. 15500-15510.
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