Cifarelli, V. | bioRxiv Science

bioRxiv2025

Sex Differences in VEGF and PDGF Ligand and Receptor Protein Expression during Adipose Tissue Expansion and Regression

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.

cell biology↗

bioRxiv2024

Insulin regulates lymphatic endothelial function via palmitoylation

Lipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. However, the role of lipid metabolism in LEC function is not well understood. Insulin is a key regulator of lipid metabolism and protein palmitoylation, the reversible post-translational protein modification by palmitate that affects protein stability, trafficking, protein-protein, and protein-membrane interactions. Human LECs are highly sensitive to insulin and can develop insulin resistance in vitro, but whether insulin regulates LEC protein palmitoylation and function is unknown. To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin regulated targets and profiled differences in palmitoylation between lymphatic and blood endothelial cells. Palmitoylation occurred primarily in proteins involved in LEC vesicular or membrane trafficking, translation initiation, and in those found in membrane rafts. Insulin enriched palmitoylation of LEC proteins involved in GTPase signaling, ubiquitination, and junctional anchoring. We also determined that the long-chain fatty acid receptor CD36 mediates optimal lymphatic palmitoylation. CD36 silencing in LECs doubled palmitoylation targets involving proteins related to inflammation and neutrophil degranulation contributing to an activated inflamed endothelium. These results suggest that the coordination of the process of palmitoylation is critical for normal lymphatic endothelial function.

physiology↗