TY - JOUR
T1 - Extracellular regulation of VEGF
T2 - Isoforms, proteolysis, and vascular patterning
AU - Vempati, Prakash
AU - Popel, Aleksander S.
AU - Mac Gabhann, Feilim
N1 - Funding Information:
Aleksander S. Popel , Ph.D., is a Professor of Biomedical Engineering at the Johns Hopkins University School of Medicine. He holds joint appointments as Professor of Oncology in the School of Medicine, and Professor of Chemical & Biomolecular Engineering in the Johns Hopkins Whiting School of Engineering. He is a member of the Institute for Nanobiotechnology, In Vivo Cellular Molecular Imaging Center, and the Sydney Kimmel Comprehensive Cancer Center. He has published over 250 scientific papers in the areas of angiogenesis and microcirculation, systems biology, computational medicine & biology. He is the recipient of the Eugene M. Landis Award from the Microcirculatory Society. He is a Fellow of the American Institute of Medical and Biological Engineering, American Heart Association, American Physiological Society, and American Society of Mechanical Engineers, and an Inaugural Fellow of the Biomedical Engineering Society. He has been a member of editorial boards of biological and biomedical engineering journals, and has served in an advisory role to biotech and pharmaceutical companies. He regularly serves on grant review boards and advisory panels at the National Institutes of Health, National Science Foundation, and other US and international funding agencies.
Funding Information:
This work was supported by the National Institutes of Health (NIH) grants R01 HL101200 and R01 CA138264 (ASP) and R00 HL093219 (FMG). The authors thank Dr. David Noren, Dr. Elena Rosca, and Dr. Marianne O. Engel-Stefanini and other members of the Popel laboratory for useful discussions and critical comments.
Funding Information:
Feilim Mac Gabhann , Ph.D., joined Johns Hopkins University as an Assistant Professor in 2009, with an appointment in Biomedical Engineering and in the Institute for Computational Medicine. He completed his PhD in Biomedical Engineering in 2007, also at Johns Hopkins University, working with Aleksander S. Popel to create mathematical models of growth factor networks in peripheral artery disease and cancer. During postdoctoral work with Shayn M. Peirce and Thomas C. Skalak at the University of Virginia, he conducted experimental research on microvascular remodeling in mouse skeletal muscle. The Mac Gabhann lab creates molecularly-detailed mathematical models of human physiology and disease, including peripheral artery disease, cancer, ALS, pre-eclampsia and HIV. The models have a particular focus on the development and testing of therapeutics. Dr. Mac Gabhann is a Sloan Research Fellow and recipient of a K99/R00 NIH Pathway to Independence Award, the 2010 August Krogh Young Investigator Award from the Microcirculatory Society, and the 2012 Arthur C. Guyton Award for Excellence in Integrative Physiology from the American Physiology Society. He is the author of 44 peer-reviewed papers, and is an Associate Editor for PLoS Computational Biology and BMC Physiology.
PY - 2014/2
Y1 - 2014/2
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
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U2 - 10.1016/j.cytogfr.2013.11.002
DO - 10.1016/j.cytogfr.2013.11.002
M3 - Review 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 -