Chordin-like 1, a bone morphogenetic protein-4 antagonist, is upregulated by hypoxia in human retinal pericytes and plays a role in regulating angiogenesis.
OBJECTIVE
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.
Kane
Rosemary
R
School of Medicine and Medical Science, UCD Conway Institute and UCD Diabetes Research Centre, University College Dublin, Belfield, Dublin 4, Ireland.
Godson
Catherine
C
O'Brien
Colm
C
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015203:Reproducibility of Results; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C486602:CHRDL1 protein, human; D005136:Eye Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A