Abstract
Nearly all studies of angiogenesis have focused on uni-family ligand-receptor binding, e.g., VEGFs bind to VEGF receptors, PDGFs bind to PDGF receptors, etc. The discovery of VEGF-PDGFRs binding challenges this paradigm and calls for investigation of other ligand-receptor binding possibilities. We utilized surface plasmon resonance to identify and measure PDGF-to-VEGFR binding rates, establishing cut-offs for binding and non-binding interactions. We quantified the kinetics of the recent VEGF-A:PDGFRβ interaction for the first time with KD = 340 pM. We discovered new PDGF:VEGFR2 interactions with PDGF-AA:R2 KD = 530 nM, PDGF-AB:R2 KD = 110 pM, PDGF-BB:R2 KD = 40 nM, and PDGF-CC:R2 KD = 70 pM. We computationally predict that cross-family PDGF binding could contribute up to 96% of VEGFR2 ligation in healthy conditions and in cancer. Together the identification, quantification, and simulation of these novel cross-family interactions posits new mechanisms for understanding anti-angiogenic drug resistance and presents an expanded role of growth factor signaling with significance in health and disease.
Highlights
Most studies of angiogenesis have focused on uni-family ligand-receptor binding, e.g., vascular endothelial growth factor (VEGF) bind to VEGF receptors, platelet derived growth factors (PDGFs) bind to PDGF receptors, etc
Incorporating a cross-family view of angiogenesis into therapeutics has led to synergistic effects and improved blood flow, when dual-growth factor therapy is applied in pre-clinical ischemia models[11], and improved wound healing, when dual-growth factors are coupled to biomaterials for tissue-engineering[12,13]
We show examples of this in PDGF:PDGFR binding (Fig. 5), and all were all found to have χ2-to-Rmax < 1.0, indicating true 1:1 Langmuir interactions (Supplementary Table S1.) There was no evidence of PDGF interactions with VEGFR1 or VEGFR3 (Supplementary Fig. S1)
Summary
Most studies of angiogenesis have focused on uni-family ligand-receptor binding, e.g., VEGFs bind to VEGF receptors, PDGFs bind to PDGF receptors, etc. Anti-angiogenic approaches have not yielded the promise of sustained vascular inhibition nor have pro-angiogenic approaches yielded stable blood vessel growth[3,4,5,6,7] This is likely due to the fact that angiogenesis involves several signaling pathways, in addition to VEGF, representing a cross-family signaling complexity that cannot be captured by targeting one growth factor alone. The canonical angiogenesis philosophy involves uni-family ligand-receptor binding: VEGFs bind to VEGFRs, PDGFs bind to PDGFRs, and so on Since VEGFs and PDGFs are both key regulators of angiogenesis, shifting the focus of angiogenesis away from a uni-family (VEGF-family alone) and towards a dual-family (VEGF and PDGF) focus would be a www.nature.com/scientificreports/
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