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

Publication ,  Journal Article
Wu, FTH; Stefanini, MO; Mac Gabhann, F; Kontos, CD; Annex, BH; Popel, AS
Published in: Am J Physiol Heart Circ Physiol
June 2010

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.

Duke Scholars

Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

June 2010

Volume

298

Issue

6

Start / End Page

H2174 / H2191

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor A
  • Signal Transduction
  • Regional Blood Flow
  • Peripheral Vascular Diseases
  • Neuropilin-1
  • Neovascularization, Pathologic
  • Muscle, Skeletal
  • Models, Biological
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wu, F. T. H., Stefanini, M. O., Mac Gabhann, F., Kontos, C. D., Annex, B. H., & Popel, A. S. (2010). VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model. Am J Physiol Heart Circ Physiol, 298(6), H2174–H2191. https://doi.org/10.1152/ajpheart.00365.2009
Wu, Florence T. H., Marianne O. Stefanini, Feilim Mac Gabhann, Christopher D. Kontos, Brian H. Annex, and Aleksander S. Popel. “VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model.Am J Physiol Heart Circ Physiol 298, no. 6 (June 2010): H2174–91. https://doi.org/10.1152/ajpheart.00365.2009.
Wu FTH, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model. Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2174–91.
Wu, Florence T. H., et al. “VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model.Am J Physiol Heart Circ Physiol, vol. 298, no. 6, June 2010, pp. H2174–91. Pubmed, doi:10.1152/ajpheart.00365.2009.
Wu FTH, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model. Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2174–H2191.

Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

June 2010

Volume

298

Issue

6

Start / End Page

H2174 / H2191

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor A
  • Signal Transduction
  • Regional Blood Flow
  • Peripheral Vascular Diseases
  • Neuropilin-1
  • Neovascularization, Pathologic
  • Muscle, Skeletal
  • Models, Biological