VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy

Renhai Cao; Yuan Xue; Eva-Maria Hedlund; Zhaodong Zhong; Katerina Tritsaris; Barbara Tondelli; Franco Lucchini; Zhenping Zhu; Steen Dissing; Yihai Cao

doi:10.1073/pnas.0911661107

VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy

Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):856-61. doi: 10.1073/pnas.0911661107. Epub 2009 Dec 22.

Authors

Renhai Cao¹, Yuan Xue, Eva-Maria Hedlund, Zhaodong Zhong, Katerina Tritsaris, Barbara Tondelli, Franco Lucchini, Zhenping Zhu, Steen Dissing, Yihai Cao

Affiliation

¹ Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / therapeutic use
Animals
Antibodies, Monoclonal
Female
Humans
Male
Mice
Mice, Inbred C57BL
Neoplasms / complications*
Neoplasms / drug therapy
Pericytes / pathology*
Placenta Growth Factor
Platelet Endothelial Cell Adhesion Molecule-1 / immunology
Pregnancy Proteins / antagonists & inhibitors
Pregnancy Proteins / physiology
Rats
Receptor, Platelet-Derived Growth Factor beta / immunology
Retina / pathology
Retinal Diseases / drug therapy
Retinal Diseases / epidemiology*
Retinal Diseases / pathology
Vascular Endothelial Growth Factor A / physiology*
Vascular Endothelial Growth Factor Receptor-1 / physiology*

Substances

Angiogenesis Inhibitors
Antibodies, Monoclonal
PGF protein, human
Pgf protein, mouse
Pgf protein, rat
Platelet Endothelial Cell Adhesion Molecule-1
Pregnancy Proteins
Vascular Endothelial Growth Factor A
Placenta Growth Factor
Receptor, Platelet-Derived Growth Factor beta
Vascular Endothelial Growth Factor Receptor-1