VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: An in silico model

Florence T.H. Wu, Marianne O. Stefanini, Feilim Mac Gabhann, Christopher D. Kontos, Brian H. Annex, Aleksander S. Popel

Research output: Contribution to journalArticle

Abstract

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, the growth of new capillaries from existing microvasculature. In peripheral arterial disease (PAD), lower extremity muscle ischemia develops downstream of atherosclerotic obstruction. A working hypothesis proposed that the maladaptive overexpression of soluble VEGF receptor 1 (sVEGFR1) in ischemic muscle tissues, and its subsequent antagonism of VEGF bioactivity, may contribute to the deficient angiogenic response in PAD, as well as the limited success of therapeutic angiogenesis strategies where exogenous VEGF genes/proteins are delivered. The objectives of this study were to develop a computational framework for simulating the systemic distributions of VEGF and sVEGFR1 (e.g., intramuscular vs. circulating, free vs. complexed) as observed in human PAD patients and to serve as a platform for the systematic optimization of diagnostic tools and therapeutic strategies. A three-compartment model was constructed, dividing the human body into the ischemic calf muscle, blood, and the rest of the body, connected through macromolecular biotransport processes. Detailed molecular interactions between VEGF, sVEGFR1, endothelial surface receptors (VEGFR1, VEGFR2, NRP1), and interstitial matrix sites were modeled. Our simulation results did not support a simultaneous decrease in plasma sVEGFR1 during PAD-associated elevations in plasma VEGF reported in literature. Furthermore, despite the overexpression in sVEGFR1, our PAD control demonstrated increased proangiogenic signaling complex formation, relative to our previous healthy control, due to sizeable upregulations in VEGFR2 and VEGF expression, thus leaving open the possibility that impaired angiogenesis in PAD may be rooted in signaling pathway disruptions downstream of ligand-receptor binding.

Original languageEnglish (US)
Pages (from-to)H2174-H2191
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number6
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

Fingerprint

Vascular Endothelial Growth Factor Receptor-1
Peripheral Arterial Disease
Computer Simulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor
Muscles
Microvessels
Human Body
Lower Extremity
Up-Regulation
Ischemia
Ligands
Therapeutics
Growth

Keywords

  • Computational model
  • Mathematical model
  • Molecular systems biology
  • Therapeutic angiogenesis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease : An in silico model. / Wu, Florence T.H.; Stefanini, Marianne O.; Mac Gabhann, Feilim; Kontos, Christopher D.; Annex, Brian H.; Popel, Aleksander S.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 298, No. 6, 01.06.2010, p. H2174-H2191.

Research output: Contribution to journalArticle

Wu, Florence T.H. ; Stefanini, Marianne O. ; Mac Gabhann, Feilim ; Kontos, Christopher D. ; Annex, Brian H. ; Popel, Aleksander S. / VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease : An in silico model. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 298, No. 6. pp. H2174-H2191.
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