Abstract
The regulation of vascular endothelial growth factor A (VEGF) is critical to neovascularization in numerous tissues under physiological and pathological conditions. VEGF has multiple isoforms, created by alternative splicing or proteolytic cleavage, and characterized by different receptor-binding and matrix-binding properties. These isoforms are known to give rise to a spectrum of angiogenesis patterns marked by differences in branching, which has functional implications for tissues. In this review, we detail the extensive extracellular regulation of VEGF and the ability of VEGF to dictate the vascular phenotype. We explore the role of VEGF-releasing proteases and soluble carrier molecules on VEGF activity. While proteases such as MMP9 can 'release' matrix-bound VEGF and promote angiogenesis, for example as a key step in carcinogenesis, proteases can also suppress VEGF's angiogenic effects. We explore what dictates pro- or anti-angiogenic behavior. We also seek to understand the phenomenon of VEGF gradient formation. Strong VEGF gradients are thought to be due to decreased rates of diffusion from reversible matrix binding, however theoretical studies show that this scenario cannot give rise to lasting VEGF gradients in vivo. We propose that gradients are formed through degradation of sequestered VEGF. Finally, we review how different aspects of the VEGF signal, such as its concentration, gradient, matrix-binding, and NRP1-binding can differentially affect angiogenesis. We explore how this allows VEGF to regulate the formation of vascular networks across a spectrum of high to low branching densities, and from normal to pathological angiogenesis. A better understanding of the control of angiogenesis is necessary to improve upon limitations of current angiogenic therapies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-19 |
| Number of pages | 19 |
| Journal | Cytokine and Growth Factor Reviews |
| Volume | 25 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- Angiogenesis
- Computational model
- Extracellular matrix
- Gradient
- Mathematical model
- Microenvironment
- Protease
- Receptor
- Systems biology
ASJC Scopus subject areas
- Immunology
- Endocrinology, Diabetes and Metabolism
- Immunology and Allergy
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Extracellular regulation of VEGF : Isoforms, proteolysis, and vascular patterning. / Vempati, Prakash; Popel, Aleksander S; Mac Gabhann, Feilim.
In: Cytokine and Growth Factor Reviews, Vol. 25, No. 1, 2014, p. 1-19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Extracellular regulation of VEGF
T2 - Isoforms, proteolysis, and vascular patterning
AU - Vempati, Prakash
AU - Popel, Aleksander S
AU - Mac Gabhann, Feilim
PY - 2014
Y1 - 2014
N2 - The regulation of vascular endothelial growth factor A (VEGF) is critical to neovascularization in numerous tissues under physiological and pathological conditions. VEGF has multiple isoforms, created by alternative splicing or proteolytic cleavage, and characterized by different receptor-binding and matrix-binding properties. These isoforms are known to give rise to a spectrum of angiogenesis patterns marked by differences in branching, which has functional implications for tissues. In this review, we detail the extensive extracellular regulation of VEGF and the ability of VEGF to dictate the vascular phenotype. We explore the role of VEGF-releasing proteases and soluble carrier molecules on VEGF activity. While proteases such as MMP9 can 'release' matrix-bound VEGF and promote angiogenesis, for example as a key step in carcinogenesis, proteases can also suppress VEGF's angiogenic effects. We explore what dictates pro- or anti-angiogenic behavior. We also seek to understand the phenomenon of VEGF gradient formation. Strong VEGF gradients are thought to be due to decreased rates of diffusion from reversible matrix binding, however theoretical studies show that this scenario cannot give rise to lasting VEGF gradients in vivo. We propose that gradients are formed through degradation of sequestered VEGF. Finally, we review how different aspects of the VEGF signal, such as its concentration, gradient, matrix-binding, and NRP1-binding can differentially affect angiogenesis. We explore how this allows VEGF to regulate the formation of vascular networks across a spectrum of high to low branching densities, and from normal to pathological angiogenesis. A better understanding of the control of angiogenesis is necessary to improve upon limitations of current angiogenic therapies.
AB - The regulation of vascular endothelial growth factor A (VEGF) is critical to neovascularization in numerous tissues under physiological and pathological conditions. VEGF has multiple isoforms, created by alternative splicing or proteolytic cleavage, and characterized by different receptor-binding and matrix-binding properties. These isoforms are known to give rise to a spectrum of angiogenesis patterns marked by differences in branching, which has functional implications for tissues. In this review, we detail the extensive extracellular regulation of VEGF and the ability of VEGF to dictate the vascular phenotype. We explore the role of VEGF-releasing proteases and soluble carrier molecules on VEGF activity. While proteases such as MMP9 can 'release' matrix-bound VEGF and promote angiogenesis, for example as a key step in carcinogenesis, proteases can also suppress VEGF's angiogenic effects. We explore what dictates pro- or anti-angiogenic behavior. We also seek to understand the phenomenon of VEGF gradient formation. Strong VEGF gradients are thought to be due to decreased rates of diffusion from reversible matrix binding, however theoretical studies show that this scenario cannot give rise to lasting VEGF gradients in vivo. We propose that gradients are formed through degradation of sequestered VEGF. Finally, we review how different aspects of the VEGF signal, such as its concentration, gradient, matrix-binding, and NRP1-binding can differentially affect angiogenesis. We explore how this allows VEGF to regulate the formation of vascular networks across a spectrum of high to low branching densities, and from normal to pathological angiogenesis. A better understanding of the control of angiogenesis is necessary to improve upon limitations of current angiogenic therapies.
KW - Angiogenesis
KW - Computational model
KW - Extracellular matrix
KW - Gradient
KW - Mathematical model
KW - Microenvironment
KW - Protease
KW - Receptor
KW - Systems biology
UR - http://www.scopus.com/inward/record.url?scp=84895806240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84895806240&partnerID=8YFLogxK
U2 - 10.1016/j.cytogfr.2013.11.002
DO - 10.1016/j.cytogfr.2013.11.002
M3 - Article
C2 - 24332926
AN - SCOPUS:84895806240
VL - 25
SP - 1
EP - 19
JO - Cytokine and Growth Factor Reviews
JF - Cytokine and Growth Factor Reviews
SN - 1359-6101
IS - 1
ER -