Cross-family Signaling: PDGF Mediates VEGFR Activation and Endothelial Function

Cross-family signaling between platelet-derived growth factors (PDGFs) and vascular endothelial growth factor receptors (VEGFRs) is a newly discovered yet unexplored mechanism of angiogenesis regulation. This study elucidates the role of PDGFs in endothelial cell (EC) signaling and functions, focusing on VEGFR1 and VEGFR2 activation. Using human dermal microvascular ECs (HDMECs) with double knockout of PDGFRα/β and human brain microvascular ECs (HBMECs), we show three key findings: (1) PDGF-AA and -BB induced VEGFR1 phosphorylation, peaking at 2-fold increases at low concentrations (0.5 ng/mL), while PDGF-AB stimulated a 2-fold rise in VEGFR2 phosphorylation. (2) Downstream effectors PLCγ1, Akt, and FAK were activated by all three PDGFs at levels comparable to VEGF-A. (3) PDGF-BB significantly enhanced EC proliferation (up to 240%) and migration (up to 170%), with lower PDGF concentrations (0.5–5 ng/mL) eliciting stronger effects than higher concentrations (50–100 ng/mL). Overall, PDGF subtypes differentially induce VEGFR phosphorylation, downstream effector activation, and angiogenic hallmarks such as proliferation and migration, revealing novel mechanisms for regulating endothelial function.