Journal
MATRIX BIOLOGY
Volume 28, Issue 5, Pages 284-291Publisher
ELSEVIER
DOI: 10.1016/j.matbio.2009.04.010
Keywords
Perlecan; Heparan sulfate proteoglycan; VEGF; VEGF receptor; Angiogenesis; Endothelial cell; Zebrafish
Categories
Funding
- NIH [RO1 CA39481, RO1 CA47282, RO1 CA120975]
- Mizutani Foundation for Glycoscience
- National Research Service Award [T32 AA07463]
- NATIONAL CANCER INSTITUTE [R01CA039481, R01CA120975, R01CA047282] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [T32AA007463] Funding Source: NIH RePORTER
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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 that 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. (C) 2009 Elsevier B.V. All rights reserved.
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