Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

被引：30

作者：

Kumar, Anil ^{[1
]}

Hou, Xu ^{[1
,3
]}

Lee, Chunsik ^{[1
]}

Li, Yang ^{[1
]}

Maminishkis, Arvydas ^{[1
]}

Tang, Zhongshu ^{[1
]}

Zhang, Fan ^{[1
]}

Langer, Harald F. ^{[2
,6
]}

Arjunan, Pachiappan ^{[1
]}

Dong, Lijin ^{[1
]}

Wu, Zhijian ^{[1
]}

Zhu, Linda Y. ^{[1
]}

Wang, Lianchun ^{[4
]}

Min, Wang ^{[5
]}

Colosi, Peter ^{[1
]}

Chavakis, Triantafyllos ^{[2
]}

Li, Xuri ^{[1
]}

机构：

[1] NEI, NIH, Rockville, MD 20852 USA

[2] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[3] Fourth Mil Med Univ, Xijing Hosp, Eye Inst Chinese PLA, Dept Ophthalmol, Xian 710032, Peoples R China

[4] Univ Georgia, Complex Carbohydrate Res Ctr, Dept Biochem & Mol Biol, Athens, GA 30602 USA

[5] Yale Univ, Dept Pathol Vasc Biol & Therapeut, New Haven, CT 06520 USA

[6] Univ Tubingen, Dept Cardiovasc Med, D-72076 Tubingen, Germany

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 20期

关键词：

SMOOTH-MUSCLE-CELLS; PDGF-D; RETINAL NEOVASCULARIZATION; INTRAVITREAL INJECTION; FACTOR VEGF; MACULAR DEGENERATION; PEGAPTANIB SODIUM; INHIBITION; EXPRESSION; SURVIVAL;

D O I：

10.1074/jbc.M110.113787

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-3 beta (GSK3 beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3 beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3 beta 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.

引用

页码：15500 / 15510

页数：11

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