VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy.
VEGF coordinates complex regulation of cellular regeneration and interactions between endothelial and perivascular cells; dysfunction of the VEGF signaling system leads to retinopathy. Here, we show that systemic delivery of VEGF and placental growth factor (PlGF) by protein implantation, tumors, and adenoviral vectors ablates pericytes from the mature retinal vasculature through the VEGF receptor 1 (VEGFR1)-mediated signaling pathway, leading to increased vascular leakage. In contrast, we demonstrate VEGF receptor 2 (VEGFR2) is primarily expressed in nonvascular photoreceptors and ganglion cells. Moreover, blockade of VEGFR1 but not VEGFR2 significantly restores pericyte saturation in mature retinal vessels. Our findings link VEGF and PlGF to cancer-associated retinopathy, reveal the molecular mechanisms of VEGFR1 ligand-mediated retinopathy, and define VEGFR1 as an important target of antiangiogenic therapy for treatment of retinopathy.
Cao
Renhai
R
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Xue
Yuan
Y
Hedlund
Eva-Maria
EM
Zhong
Zhaodong
Z
Tritsaris
Katerina
K
Tondelli
Barbara
B
Lucchini
Franco
F
Zhu
Zhenping
Z
Dissing
Steen
S
Cao
Yihai
Y
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D020286:Pericytes / Q000473:pathology*; D000072483:Placenta Growth Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000276:immunology; D012160:Retina / Q000473:pathology; D012164:Retinal Diseases / Q000188:drug therapy / Q000453:epidemiology* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; C000608038:Pgf protein, rat; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D040281:Vascular Endothelial Growth Factor Receptor-1