Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5.
We have previously shown that intravitreal injection of plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibits ischemia-induced retinal neovascularization in a rat model. Here we report that K5 down-regulates an endogenous angiogenic stimulator, vascular endothelial growth factor (VEGF) and up-regulates an angiogenic inhibitor, pigment epithelium-derived factor (PEDF) in a dose-dependent manner in vascular cells and in the retina. The regulation of VEGF and PEDF by K5 in the retina correlates with its anti-angiogenic effect in a rat model of ischemia-induced retinopathy. Retinal RNA levels of VEGF and PEDF are also changed by K5. K5 inhibits the p42/p44 MAP kinase activation and nuclear translocation of hypoxia-inducible factor-1alpha, which may be responsible for the down-regulation of VEGF. Down-regulation of endogenous angiogenic stimulators and up-regulation of endogenous angiogenic inhibitors, thus leading toward restoration of the balance in angiogenic control, may represent a mechanism for the anti-angiogenic activity of K5.
Gao
Guoquan
G
Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina 29403, USA.
Li
Yan
Y
Gee
Stephen
S
Dudley
Andrew
A
Fant
James
J
Crosson
Craig
C
Ma
Jian-xing
JX
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005136:Eye Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018082:Kringles; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009414:Nerve Growth Factors; D010766:Phosphorylation; D010958:Plasminogen / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012160:Retina / Q000378:metabolism; D015861:Retinal Neovascularization; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099174:Pigment Epithelium-Derived Factor
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D005136:Eye Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D020928:Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors; D010958:Plasminogen; D011506:Proteins; D012333:RNA, Messenger; D015843:Serpins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099174:Pigment Epithelium-Derived Factor