Systems Pharmacology of VEGF165b in Peripheral Artery Disease

<jats:p>We built a whole‐body computational model to study the role of the poorly understood vascular endothelial growth factor (VEGF)<jats:sub>165b</jats:sub> 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<jats:sub>165b</jats:sub>: lack of extracellular matrix (ECM)‐binding and weak phosphorylation of vascular endothelial growth factor receptor‐2 (VEGFR2) <jats:italic>in vitro</jats:italic>. The resulting model captures all known information about VEGF<jats:sub>165b</jats:sub> distribution and signaling in human PAD, and provides novel, nonintuitive insight into VEGF<jats:sub>165b</jats:sub> mechanism of action <jats:italic>in vivo</jats:italic>. Although VEGF<jats:sub>165a</jats:sub> and VEGF<jats:sub>165b</jats:sub> compete for VEGFR2 <jats:italic>in vitro</jats:italic>, simulations show that these isoforms do not compete for VEGFR2 at much lower physiological concentrations. Instead, reduced VEGF<jats:sub>165a</jats:sub> may drive impaired VEGFR2 signaling. The model predicts that VEGF<jats:sub>165b</jats:sub> does compete for binding to VEGFR1, supporting a VEGFR1‐mediated response to anti‐VEGF<jats:sub>165b</jats:sub>. The model predicts a key role for VEGF<jats:sub>165b</jats:sub> in PAD, but in a different way than previously hypothesized.</jats:p>