Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy

Feilim Mac Gabhann, James W. Ji, Aleksander S Popel

Research output: Contribution to journalArticle

Abstract

Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 μm) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of proangiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 μm) is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 μm long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)1107-1120
Number of pages14
JournalPLoS Computational Biology
Volume2
Issue number9
DOIs
StatePublished - 2006

Fingerprint

Endothelial Factors
vascular endothelial growth factors
Growth Factors
Cell- and Tissue-Based Therapy
Spatial Distribution
Muscle
Computational Model
Spatial distribution
Vascular Endothelial Growth Factor A
Therapy
muscle
spatial distribution
Muscles
muscles
therapeutics
Cell
cells
vascular endothelial growth factor receptors
Gradient
Vascular Endothelial Growth Factor Receptor

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Computational Theory and Mathematics

Cite this

Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy. / Gabhann, Feilim Mac; Ji, James W.; Popel, Aleksander S.

In: PLoS Computational Biology, Vol. 2, No. 9, 2006, p. 1107-1120.

Research output: Contribution to journalArticle

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