Towards Novel Angiogenesis Therapies: Explorations of Non-Canonical Angiogenic Signaling (INVITED SPEAKER)

Several diseases are attributed to either deficient or excessive vascularization, so understanding angiogenesis offers great promise for improving vascular therapies. We recently discovered non-canonical, high-affinity binding of platelet derived growth factors (PDGFs) to the primary angiogenic receptor, vascular endothelial growth factor receptor-2 (VEGFR2). Delineating this currently undefined PDGF role in VEGFR2 signaling will provide new tactics for controlling angiogenesis in health and disease. Towards this aim, we computationally model binding and trafficking; experimentally measure signaling and angiogenic function; and molecular interactions. Our mass-action kinetics models predict significant PDGF:VEGFR2 binding when VEGFR2 is overexpressed and during anti-VEGF therapy. Our signaling assays reveal selective activation of VEGFR2 and activation of the common angiogenic signaling molecules: Src kinase (Src), focal adhesion kinase (FAK), phospholipase-Cγ (PLCγ), and phosphoinositide 3-kinase (PI3K). Furthermore, PDGF treatment induces cell proliferation, an angiogenic hallmark, and select PDGFs mediate cell migration. Finally, stable PDGF:VEGFR2 binding conformations are observed via molecular dynamics (MD) simulations. Our modeling, signaling, and functional analyses define the importance of PDGF:VEGFR2 signaling. Further exploration of this non-canonical signaling should drive the development of new treatments for angiogenesis-related diseases.

Acknowledgements: This material is based upon work supported by the National Science Foundation (NSF) and American Heart Association (AHA) under grant numbers: NSF CAREER: 1653925; NSF BPE: 1648454; and AHA:16SDG26940002.