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Open AccessArticle

Hypoxia Induced Heparan Sulfate Primes the Extracellular Matrix for Endothelial Cell Recruitment by Facilitating VEGF-Fibronectin Interactions

1
Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
2
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02215, USA
3
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 5065; https://doi.org/10.3390/ijms20205065
Received: 9 September 2019 / Revised: 7 October 2019 / Accepted: 9 October 2019 / Published: 12 October 2019
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 2.0)
Vascular endothelial growth factor-A (VEGF) is critical for the development, growth, and survival of blood vessels. Retinal pigmented epithelial (RPE) cells are a major source of VEGF in the retina, with evidence that the extracellular matrix (ECM)-binding forms are particularly important. VEGF associates with fibronectin in the ECM to mediate distinct signals in endothelial cells that are required for full angiogenic activity. Hypoxia stimulates VEGF expression and angiogenesis; however, little is known about whether hypoxia also affects VEGF deposition within the ECM. Therefore, we investigated the role of hypoxia in modulating VEGF-ECM interactions using a primary retinal cell culture model. We found that retinal endothelial cell attachment to RPE cell layers was enhanced in cells maintained under hypoxic conditions. Furthermore, we found that agents that disrupt VEGF-fibronectin interactions inhibited endothelial cell attachment to RPE cells. We also found that hypoxia induced a general change in the chemical structure of the HS produced by the RPE cells, which correlated to changes in the deposition of VEGF in the ECM, and we further identified preferential binding of VEGFR2 over VEGFR1 to VEGF laden-fibronectin matrices. Collectively, these results indicate that hypoxia-induced HS may prime fibronectin for VEGF deposition and endothelial cell recruitment by promoting VEGF-VEGFR2 interactions as a potential means to control angiogenesis in the retina and other tissues. View Full-Text
Keywords: age-related macular degeneration; angiogenesis; endothelial cell; fibronectin; hypoxia; retina; vascular endothelial growth factor age-related macular degeneration; angiogenesis; endothelial cell; fibronectin; hypoxia; retina; vascular endothelial growth factor
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Buczek-Thomas, J.A.; Rich, C.B.; Nugent, M.A. Hypoxia Induced Heparan Sulfate Primes the Extracellular Matrix for Endothelial Cell Recruitment by Facilitating VEGF-Fibronectin Interactions. Int. J. Mol. Sci. 2019, 20, 5065.

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