Open AccessSystems Pharmacology of VEGF165b in Peripheral Artery Disease
Author(s) -
Clegg Lindsay E.,
Ganta Vijay C.,
Annex Brian H.,
Mac Gabhann Feilim
Publication year - 2017
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12261
Subject(s) - in vitro , in vivo , phosphorylation , gene isoform , kinase insert domain receptor , pharmacology , vascular endothelial growth factor , microbiology and biotechnology , extracellular matrix , ex vivo , signal transduction , extracellular , chemistry , vegf receptors , medicine , cancer research , biology , vascular endothelial growth factor a , biochemistry , genetics , gene
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.