Beneficial effects of vascular endothelial growth factor B gene transfer in the aged heartManickam, Sultan, Panthel
et alCardiovasc Res (2025)
Abstract: Members of the VEGF family are crucial modulators of vascular and neural function. While VEGFA signaling has been shown to mitigate several aging-related cardiac phenotypes and prolong survival in aged mice, the role of VEGFB in cardiac aging remains underexplored. In this study, we identify a significant decline in Vegfb expression, particularly of its soluble isoform Vegfb186, in aged mouse and human hearts. To assess the therapeutic potential of VEGFB in aging-associated cardiac pathologies, we used AAV9-mediated gene transfer to overexpress Vegfb186 in 18-month-old male C57Bl/6J mice.VEGFB is known to exhibit vascular and neuroprotective effects that we assessed in the ageing heart. In the aged heart, doses of Vegfb186 overexpression that had only a modest effect on the vascular endothelium prevented age-induced diastolic dysfunction and fibrosis. Vegfb186 treatment additionally restored sympathetic and sensory nerve fiber density and increased heart rate variability. Although Vegfb186 overexpression induced cardiac hypertrophy, our findings indicated that this hypertrophy was compensatory rather than pathological as Vegfb186 overexpression corrected the elevated cardiomyocyte length-to-width-ratio observed in aged hearts, a metric typically indicative of pathological remodeling. Cardiac single-nucleus RNA sequencing of the hearts and in vitro analysis of the cardiomyocytes indicated upregulation of the STAT3 signal transduction pathway as a potential contributor of VEGFB-induced cardiac hypertrophy.Our findings demonstrate that Vegfb186 overexpression partially reverses age-related cardiac pathologies such as diastolic dysfunction and fibrosis. This work highlights VEGFB as a potential therapeutic target for combating cardiac aging and its associated dysfunctions.© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.
Cross-family interactions of vascular endothelial growth factors and platelet-derived growth factors on the endothelial cell surface: A computational modelLee, Fang, Kuila
et albioRxiv (2025)
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.New 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.
VEGF-B is a novel mediator of endoplasmic reticulum stress which induces angiogenesis in the heart without VEGFR1 or NRP activities via RGD-binding integrinsMallick, Montaser, Komi
et alMol Ther (2025)
Abstract: Vascular endothelial growth factor B186 (VEGF-B186), a ligand for VEGF receptor 1 (VEGFR1) and neuropilin (NRP), promotes vascular growth in healthy and ischemic myocardium. However, the mechanisms and signaling of VEGF-B186 to support angiogenesis have remained unclear. We studied the effects of VEGF-B186 and its variant, VEGF-B186R127S, which cannot bind to NRPs, using VEGFR1 tyrosine kinase knockout (TK-/-) mice to explore the mechanism of VEGF-B186 in promoting vascular growth. Ultrasound-guided adenoviral VEGF-B186, VEGF-B186R127S, and control vector gene transfers were performed into VEGFR1 TK-/- mice hearts. In vitro studies in cardiac endothelial cells and further validation in normal and ischemic pig hearts, as well as in wild-type mice, were conducted. Both VEGF-B186 forms promoted vascular growth in VEGFR1 TK-/- mouse heart and increased the expression of proangiogenic and hematopoietic factors. Unlike VEGF-A, VEGF-B186 forms induced ER stress via the upregulation of Binding immunoglobulin Protein (BiP) as well as ER stress sensors (ATF6, PERK, IRE1α) through ITGAV and ITGA5 integrins, newly identified receptors for VEGF-B, activating the unfolded protein response (UPR) through XBP1. VEGFR1 and NRP are not essential for VEGF-B186-induced vascular growth. Instead, VEGF-B186 can stimulate cardiac regeneration through RGD-binding integrins and ER stress, suggesting a novel mechanism of action for VEGF-B186.Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
Luminescent sensing of conformational integrin activation in living cellsVillari, Gioelli, Gino
et alCell Rep (2025) 44 (2), 115319
Abstract: Integrins are major receptors for secreted extracellular matrix, playing crucial roles in physiological and pathological contexts, such as angiogenesis and cancer. Regulation of the transition between inactive and active conformation is key for integrins to fulfill their functions, and pharmacological control of those dynamics may have therapeutic applications. We create and validate a prototypic luminescent β1 integrin activation sensor (β1IAS) by introducing a split luciferase into an activation reporting site between the βI and the hybrid domains. As a recombinant protein in both solution and living cells, β1IAS accurately reports β1 integrin activation in response to (bio)chemical and physical stimuli. A short interfering RNA (siRNA) high-throughput screening on live β1IAS knockin endothelial cells unveils hitherto unknown regulators of β1 integrin activation, such as β1 integrin inhibitors E3 ligase Pja2 and vascular endothelial growth factor B (VEGF-B). This split-luciferase-based strategy provides an in situ label-free measurement of integrin activation and may be applicable to other β integrins and receptors.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
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