An official website of the United States government
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.
more »
« less
This content will become publicly available on February 16, 2026
Sex Differences in VEGF and PDGF Ligand and Receptor Protein Expression during Adipose Tissue Expansion and Regression
ABSTRACT Inadequate angiogenesis in obesogenic adipose tissue (AT) has been implicated in disrupted adipogenesis and metabolic disorders. Yet, key cellular and molecular regulators of AT angiogenesis remain largely unidentified. This study sought to identify the dysregulated elements within the Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF) systems during obesity progression. We employ a mouse model, comprising both male and female mice, to investigate the changes in the VEGF/PDGF concentration and their receptor distribution in AT during short- and long-term weight gain and weight loss. Our results reveal pronounced sex-specific differences in obesity progression, with male and female mice exhibiting distinct angiogenic ligand and receptor profiles under identical dietary interventions. This data also lays the groundwork for developing computational models of VEGF/PDGF signaling networks in AT, allowing for the simulation of complex biological interactions and the prediction of therapeutic outcomes.
more »
« less
- Award ID(s):
- 2344705
- PAR ID:
- 10580593
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Obesity is a global health crisis, with its prevalence particularly severe in the United States, where over 42% of adults are classified as obese. Obesity is driven by complex molecular and tissue-level mechanisms that remain poorly understood. Among these, angiogenesis—primarily mediated by vascular endothelial growth factor (VEGF-A)—is critical for adipose tissue expansion but presents unique challenges for therapeutic targeting due to its intricate regulation. Systems biology approaches have advanced our understanding of VEGF-A signaling in vascular diseases, but their application to obesity is limited by scattered and sometimes contradictory data. To address this gap, we performed a comprehensive analysis of the existing literature to synthesize key findings, standardize data, and provide a holistic perspective on the adipose vascular microenvironment. The data mining revealed five key findings: (1) obesity increases adipocyte size by 78%; (2) vessel density in adipose tissue decreases by 51% in obese mice, with vessels being 47–58% smaller and 4–9 times denser in comparison with tumor vessels; (3) capillary basement membrane thickness remains similar regardless of obesity; (4) VEGF-A shows the strongest binding affinity for VEGFR1, with four times stronger affinity for VEGFR2 than for NRP1; and (5) binding affinities measured by radioligand binding assay and surface plasmon resonance (SPR) are significantly different. These consolidated findings provide essential parameters for systems biology modeling, new insights into obesity-induced changes in adipose tissue, and a foundation for developing angiogenesis-targeting therapies for obesity.more » « less
-
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.more » « less
-
null (Ed.)Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor–β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator–activated receptor–γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.more » « less
-
Abstract Chronic wounds are one of the most devastating complications of diabetes and are the leading cause of nontraumatic limb amputation. Despite the progress in identifying factors and promising in vitro results for the treatment of chronic wounds, their clinical translation is limited. Given the range of disruptive processes necessary for wound healing, different pharmacological agents are needed at different stages of tissue regeneration. This requires the development of wearable devices that can deliver agents to critical layers of the wound bed in a minimally invasive fashion. Here, for the first time, a programmable platform is engineered that is capable of actively delivering a variety of drugs with independent temporal profiles through miniaturized needles into deeper layers of the wound bed. The delivery of vascular endothelial growth factor (VEGF) through the miniaturized needle arrays demonstrates that, in addition to the selection of suitable therapeutics, the delivery method and their spatial distribution within the wound bed is equally important. Administration of VEGF to chronic dermal wounds of diabetic mice using the programmable platform shows a significant increase in wound closure, re‐epithelialization, angiogenesis, and hair growth when compared to standard topical delivery of therapeutics.more » « less
