Chordin-like 1, a bone morphogenetic protein-4 antagonist, is upregulated by hypoxia in human retinal pericytes and plays a role in regulating angiogenesis.

Abstract

PURPOSE:

Pericytes play a specialized role in regulating angiogenesis and vascular function by providing vascular stability and controlling endothelial cell proliferation. Disorders in pericyte function and pericyte-endothelial interaction have been observed in several disease states including tumor angiogenesis and diabetic microangiopathy. In ischemic retinal disease, hypoxia is a potent driver of retinal angiogenesis. This study investigated the effects of hypoxia on retinal pericyte gene expression, and demonstrates a role in angiogenesis regulation for the hypoxia driven gene, chordin-like 1 (CHL-1).

METHODS:

In the current studies, we investigated hypoxia-induced gene expression in human retinal pericytes and found that expression of CHL-1, a member of the bone morphogenetic protein (BMP) superfamily, is upregulated by hypoxia. We investigated regulation of CHL-1 expression and the ability of CHL-1 to antagonize the antiangiogenic properties of BMP-4 using a human cell-based angiogenesis assay.

RESULTS:

We report that hypoxia induced hypoxia inducible factor-1alpha-driven expression of CHL-1. Both CHL-1 and BMP-4 were secreted from human retinal pericytes. We found that CHL-1 complexes with BMP-4 to antagonize the antiangiogenic effects of BMP-4, and that BMP-4 and vascular endothelial growth factor (VEGF) co-regulate angiogenesis.

CONCLUSIONS:

We propose that hypoxia-induced upregulation of CHL-1 alters the homeostatic balance between BMP-4 and VEGF to synergize with VEGF in driving retinal angiogenesis.

• Authors: Rosemary Kane, Catherine Godson, Colm O'Brien
• Journal: Molecular vision (Mol Vis) Vol. 14 Pg. 1138-48 (Jun 20 2008) ISSN: 1090-0535 [Electronic] United States
• PMID: 18587495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMP4 protein, human
• Bone Morphogenetic Protein 4
• Bone Morphogenetic Proteins
• CHRDL1 protein, human
• Eye Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nerve Tissue Proteins
• VEGFA protein, human
• Vascular Endothelial Growth Factor A

Topics

• Bone Morphogenetic Protein 4
• Bone Morphogenetic Proteins (antagonists & inhibitors, pharmacology)
• Cell Hypoxia (drug effects)
• Cells, Cultured
• Eye Proteins (genetics, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Molecular Sequence Data
• Neovascularization, Physiologic (drug effects)
• Nerve Tissue Proteins (genetics, metabolism)
• Pericytes (cytology, drug effects, metabolism)
• Protein Binding (drug effects)
• Reproducibility of Results
• Retina (cytology, drug effects, metabolism)
• Transcriptional Activation (drug effects)
• Up-Regulation (drug effects)
• Vascular Endothelial Growth Factor A (pharmacology)