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1. The role of shear stress and altered tissue properties on endothelial to mesenchymal transformation and tumor-endothelial cell interaction

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   Mina, Sara G.; Huang, Peter; Murray, Bruce T.; Mahler, Gretchen J. (July 2017, Biomicrofluidics)
2. Endothelial glycocalyx sensitivity to chemical and mechanical sub-endothelial substrate properties

   https://doi.org/10.3389/fbioe.2023.1250348  

   Hamrangsekachaee, Mohammad; Wen, Ke; Yazdani, Narges; Willits, Rebecca K; Bencherif, Sidi A; Ebong, Eno E (October 2023, Frontiers in Bioengineering and Biotechnology)

   Glycocalyx (GCX) is a carbohydrate-rich structure that coats the surface of endothelial cells (ECs) and lines the blood vessel lumen. Mechanical perturbations in the vascular environment, such as blood vessel stiffness, can be transduced and sent to ECs through mechanosensors such as GCX. Adverse stiffness alters GCX-mediated mechanotransduction and leads to EC dysfunction and eventually atherosclerotic cardiovascular diseases. To understand GCX-regulated mechanotransduction events, anin vitromodel emulatingin vivovessel conditions is needed. To this end, we investigated the impact of matrix chemical and mechanical properties on GCX expression via fabricating a tunable non-swelling matrix based on the collagen-derived polypeptide, gelatin. To study the effect of matrix composition, we conducted a comparative analysis of GCX expression using different concentrations (60–25,000 μg/mL) of gelatin and gelatin methacrylate (GelMA) in comparison to fibronectin (60 μg/mL), a standard coating material for GCX-related studies. Using immunocytochemistry analysis, we showed for the first time that different substrate compositions and concentrations altered the overall GCX expression on human umbilical vein ECs (HUVECs). Subsequently, GelMA hydrogels were fabricated with stiffnesses of 2.5 and 5 kPa, representing healthy vessel tissues, and 10 kPa, corresponding to diseased vessel tissues. Immunocytochemistry analysis showed that on hydrogels with different levels of stiffness, the GCX expression in HUVECs remained unchanged, while its major polysaccharide components exhibited dysregulation in distinct patterns. For example, there was a significant decrease in heparan sulfate expression on pathological substrates (10 kPa), while sialic acid expression increased with increased matrix stiffness. This study suggests the specific mechanisms through which GCX may influence ECs in modulating barrier function, immune cell adhesion, and mechanotransduction function under distinct chemical and mechanical conditions of both healthy and diseased substrates. 

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3. Modeling the blood–brain barrier: Beyond the endothelial cells

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   Gastfriend, Benjamin D.; Palecek, Sean P.; Shusta, Eric V. (March 2018, Current Opinion in Biomedical Engineering)
4. N-Cadherin Targeted Melanin Nanoparticles Reverse the Endothelial–Mesenchymal Transition in Vascular Endothelial Cells to Potentially Slow the Progression of Atherosclerosis and Cancer

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   Liu, Jinyuan; Yu, Xiao; Braucht, Annaliese; Smith, Steve; Wang, Congzhou (March 2024, ACS Nano)
5. Cross-family interactions of vascular endothelial growth factors and platelet-derived growth factors on the endothelial cell surface: A computational model

   https://doi.org/10.1101/2025.02.27.640640  

   Lee, Yunjeong; Fang, Yingye; Kuila, Shobhan; Imoukhuede, Princess I (March 2025, bioRxiv)

   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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