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.

Towards novel angiogenesis therapies: Explorations of non-canonical angiogenic signaling

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.