Systems pharmacology of VEGF165b in peripheral artery disease

Lindsay E. Clegg, Vijay C. Ganta, Brian H. Annex, Feilim Mac Gabhann

Research output: Contribution to journalArticle

Abstract

We built a whole-body computational model to study the role of the poorly understood vascular endothelial growth factor (VEGF) 165b splice isoform in peripheral artery disease (PAD). This model was built and validated using published and new experimental data from cells, mice, and humans, and explicitly accounts for known properties of VEGF 165b : lack of extracellular matrix (ECM)-binding and weak phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR2) in vitro. The resulting model captures all known information about VEGF 165b distribution and signaling in human PAD, and provides novel, nonintuitive insight into VEGF 165b mechanism of action in vivo. Although VEGF 165a and VEGF 165b compete for VEGFR2 in vitro, simulations show that these isoforms do not compete for VEGFR2 at much lower physiological concentrations. Instead, reduced VEGF 165a may drive impaired VEGFR2 signaling. The model predicts that VEGF 165b does compete for binding to VEGFR1, supporting a VEGFR1-mediated response to anti-VEGF 165b . The model predicts a key role for VEGF 165b in PAD, but in a different way than previously hypothesized.

Original languageEnglish (US)
Pages (from-to)833-844
Number of pages12
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume6
Issue number12
DOIs
StatePublished - Dec 2017
Externally publishedYes

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Endothelial Factors
Pharmacology
Peripheral Arterial Disease
Growth Factors
Arteries
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
Receptor
Protein Isoforms
Intercellular Signaling Peptides and Proteins
Predict
Extracellular Matrix
Phosphorylation

ASJC Scopus subject areas

  • Modeling and Simulation
  • Pharmacology (medical)

Cite this

Systems pharmacology of VEGF165b in peripheral artery disease. / Clegg, Lindsay E.; Ganta, Vijay C.; Annex, Brian H.; Gabhann, Feilim Mac.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 6, No. 12, 12.2017, p. 833-844.

Research output: Contribution to journalArticle

Clegg, Lindsay E. ; Ganta, Vijay C. ; Annex, Brian H. ; Gabhann, Feilim Mac. / Systems pharmacology of VEGF165b in peripheral artery disease. In: CPT: Pharmacometrics and Systems Pharmacology. 2017 ; Vol. 6, No. 12. pp. 833-844.
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