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Abstract Angiogenesis, the formation of new vessels from existing vessels, is mediated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Despite discoveries supporting the cross-family interactions between VEGF and PDGF families, sharing the binding partners between them makes it challenging to identify growth factors that predominantly affect angiogenesis. Systems biology offers promises to untangle this complexity. Thus, in this study, we developed a mass-action kinetics-based computational model for cross-family interactions between VEGFs (VEGF-A, VEGF-B, and PlGF) and PDGFs (PDGF-AA, PDGF-AB, and PDGF-BB) with their receptors (VEGFR1, VEGFR2, NRP1, PDGFRα, and PDGFRβ). The model, parametrized with our literature mining and surface resonance plasmon assays, was validated by comparing the concentration of VEGFR1 complexes with a previously constructed angiogenesis model. The model predictions include five outcomes: 1) the percentage of free or bound ligands and 2) receptors, 3) the concentration of free ligands, 4) the percentage of ligands occupying each receptor, and 5) the concentration of ligands that is bound to each receptor. We found that at equimolar ligand concentrations (1 nM), PlGF and VEGF-A were the main binding partners of VEGFR1 and VEGFR2, respectively. Varying the density of receptors resulted in the following five outcomes: 1) Increasing VEGFR1 density depletes the free PlGF concentration, 2) increasing VEGFR2 density decreases PDGF:PDGFRα complexes, 3) increased NRP1 density generates a biphasic concentration of the free PlGF, 4) increased PDGFRα density increases PDGFs:PDGFRα binding, and 5) increasing PDGFRβ density increases VEGF-A:PDGFRβ. Our model offers a reproducible, fundamental framework for exploring cross-family interactions that can be extended to the tissue level or intracellular molecular level. Also, our model may help develop therapeutic strategies in pathological angiogenesis by identifying the dominant complex in the cell signaling. Author summaryNew blood vessel formation from existing ones is essential for growth, healing, and reproduction. However, when this process is disrupted—either too much or too little—it can contribute to diseases such as cancer and peripheral arterial disease. Two key families of proteins, vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs), regulate this process. Traditionally, scientists believed that VEGFs only bind to VEGF receptors and PDGFs to PDGF receptors. However, recent findings show that these proteins can interact with each other’s receptors, making it more challenging to understand and control blood vessel formation. To clarify these complex interactions, we combined computer modeling with biological data to map out which proteins bind to which receptors and to what extent. Our findings show that when VEGFs and PDGFs are present in equal amounts, VEGFs are the primary binding partners for VEGF receptors. We also explored how changes in receptor levels affect these interactions in disease-like conditions. This work provides a foundational computational model for studying cross-family interactions, which can be expanded to investigate tissue-level effects and processes inside cells. Ultimately, our model may help develop better treatments for diseases linked to abnormal blood vessel growth by identifying key protein-receptor interactions.
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This content will become publicly available on March 5, 2026
Cross-family Signaling: PDGF Mediates VEGFR Activation and Endothelial Function
Abstract 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 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, achieving approximately 70% of VEGF-A’s effects. (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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- Award ID(s):
- 2344705
- PAR ID:
- 10580604
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
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