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March 5th, 2025
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University of Washington
bioengineering
biorxiv

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

Liu, X.Open in Google Scholar•Fang, Y.Open in Google Scholar•Imoukhuede, P.Open in Google Scholar

A recently discovered but unexplored mechanism of angiogenesis regulation is cross-family binding between platelet-derived growth factors (PDGFs) and vascular endothelial growth factor receptors (VEGFRs), which suggests a novel therapy for addressing vascular dysregulation. This study elucidates the role of PDGFs in endothelial cell (EC) signaling and functions, focusing on VEGFR activation. Using human dermal microvascular ECs (HDMECs) with double knockout of PDGFRalpha and PDGFRbeta; 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 PLCgamma, 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.

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