PUBLICATION
Perlecan regulates developmental angiogenesis by modulating the VEGF-VEGFR2 axis
- Authors
- Zoeller, J.J., Whitelock, J.M., and Iozzo, R.V.
- ID
- ZDB-PUB-090511-20
- Date
- 2009
- Source
- Matrix biology : journal of the International Society for Matrix Biology 28(5): 284-291 (Journal)
- Registered Authors
- Iozzo, Renato
- Keywords
- Perlecan, Heparan sulfate proteoglycan, VEGF, VEGF receptor, Angiogenesis, Endothelial cell, Zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Endothelial Cells/cytology
- Endothelial Cells/metabolism
- Gene Knockdown Techniques
- Heparan Sulfate Proteoglycans/genetics
- Heparan Sulfate Proteoglycans/metabolism*
- Humans
- Neovascularization, Physiologic/physiology
- Phenotype
- Protein Binding
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
- Signal Transduction/physiology*
- Vascular Endothelial Growth Factor A/metabolism*
- Vascular Endothelial Growth Factor Receptor-2/metabolism*
- Zebrafish*/anatomy & histology
- Zebrafish*/embryology
- Zebrafish*/metabolism
- PubMed
- 19422911 Full text @ Matrix Biol.
Citation
Zoeller, J.J., Whitelock, J.M., and Iozzo, R.V. (2009) Perlecan regulates developmental angiogenesis by modulating the VEGF-VEGFR2 axis. Matrix biology : journal of the International Society for Matrix Biology. 28(5):284-291.
Abstract
Using the zebrafish, we previously identified a central function for perlecan during angiogenic blood vessel development. Here, we explored the nature of perlecan function during developmental angiogenesis. A close examination of individual endothelial cell behavior revealed that perlecan is required for proper endothelial cell migration and proliferation. Because these events are largely mediated by VEGF-VEGFR2 signaling, we investigated the relationship between perlecan and the VEGF pathway. We discovered that perlecan knockdown caused an abnormal increase and redistribution of total VEGF-A protein suggesting perlecan is required for the appropriate localization of VEGF-A. Importantly, we linked perlecan function to the VEGF pathway by efficiently rescuing the perlecan morphant phenotype by microinjecting VEGF-A(165) protein or mRNA. Combining the strategic localization of perlecan throughout the vascular basement membrane along with its growth factor-binding ability, we hypothesized a major role for perlecan during the establishment of the VEGF gradient which provides the instructive cues to endothelial cells during angiogenesis. In support of this hypothesis we demonstrated that human perlecan bound in a heparan sulfate-dependent fashion to VEGF-A(165). Moreover, perlecan enhanced VEGF mediated VEGFR2 activation of human endothelial cells. Collectively, our results indicate that perlecan coordinates developmental angiogenesis through modulation of VEGF-VEGFR2 signaling events. The identification of angiogenic factors, such as perlecan, and their role in vertebrate development will not only enhance overall understanding of the molecular basis of angiogenesis, but may also provide new insight into angiogenesis-based therapeutic approaches.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping