Systems Pharmacology of VEGF165b in Peripheral Artery Disease

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.