Multimerin-2 orchestrates the cross-talk between endothelial cells and pericytes: A mechanism to maintain vascular stability

Fejza, Albina; Poletto, Evelina; Carobolante, Greta; Camicia, Lucrezia; Andreuzzi, Eva; Capuano, Alessandra; Pivetta, Eliana; Pellicani, Rosanna; Colladel, Roberta; Marastoni, Stefano; Doliana, Roberto; Iozzo, Renato V.; Spessotto, Paola; Mongiat, Maurizio

doi:10.1016/j.mbplus.2021.100068

Cited by 10 publications

(11 citation statements)

References 65 publications

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“…S10), indicating flow-induced adaptation and alterations in cell matrix adhesion, which ultimately resulted in matrix remodeling. In addition, multimerin 2, an EVM molecule that enhances vascular stability and regulates permeability by strengthening endothelial junctions (68,69), was found enriched in flow-conditioned tissues, suggesting a protective function in maintaining vessel function and longevity under mechanical shear stress. The substantial increase of prothrombin, which serves as a precursor to thrombin and facilitates fibrin formation (70), provides further evidence of flow-induced enhancements in EVM rigidity and subsequent matrix stabilization.…”

Section: Discussionmentioning

confidence: 99%

Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability

Cherubini,

Erickson,

Padmanaban

et al. 2023

Sci. Adv.

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Proper placental vascularization is vital for pregnancy outcomes, but assessing it with animal models and human explants has limitations. We introduce a 3D in vitro model of human placenta terminal villi including fetal mesenchyme and vascular endothelium. By coculturing HUVEC, placental fibroblasts, and pericytes in a macrofluidic chip with a flow reservoir, we generate fully perfusable fetal microvessels. Pressure-driven flow facilitates microvessel growth and remodeling, resulting in early formation of interconnected and lasting placental-like vascular networks. Computational fluid dynamics simulations predict shear forces, which increase microtissue stiffness, decrease diffusivity, and enhance barrier function as shear stress rises. Mass spectrometry analysis reveals enhanced protein expression with flow, including matrix stability regulators, proteins associated with actin dynamics, and cytoskeleton organization. Our model provides a powerful tool for deducing complex in vivo parameters, such as shear stress on developing vascularized placental tissue, and holds promise for unraveling gestational disorders related to the vasculature.

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Section: Discussionmentioning

confidence: 99%

Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability

Cherubini,

Erickson,

Padmanaban

et al. 2023

Sci. Adv.

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“… 45 More important, two recent studies further elucidated the mechanism in detail. Fejza et al 46 reported that MMRN2 is also deposited in juxtaposition between ECs and pericytes as a homeostatic molecule deposited in the later stages of vessel formation and is required to maintain vascular stability. A study by Pellicani et al 31 further indicated that MMRN2 is a key molecule required to maintain vascular stability.…”

Section: Discussionmentioning

confidence: 99%

The CXCR4/miR-1910-5p/MMRN2 Axis Is Involved in Corneal Neovascularization by Affecting Vascular Permeability

Wang

Cui

Chen

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Chemokine receptor 4 (CXCR4) plays an essential role in the early stage of corneal neovascularization (CNV), but the underlying key molecular mechanism has yet to be addressed. This study aimed to explore the new molecular mechanism of CXCR4 in CNV and the related pathological events. Methods CXCR4 was assayed by immunofluorescence or Western blotting. The function of the supernatant from hypoxia-treated human corneal epithelial cells (HCE-T) cells was examined by culturing with human umbilical vein endothelial cells. MicroRNA sequencing was used to detect the downstream microRNAs upon CXCR4 knockdown and analyzed by preliminary bioinformatics. The proangiogenic functions and downstream target genes of microRNA were investigated by gene interference and luciferase assay. An alkali-burned murine model was introduced to examine the function and mechanism of miR-1910-5p in vivo. Results High CXCR4 expression was confirmed in corneal tissues of patients with CNV and hypoxic HCE-T cells. The supernatant from hypoxia-treated HCE-T cells is involved in the CXCR4-mediated angiogenesis of human umbilical vein endothelial cells. Notably, miR-1910-5p was demonstrated to be at a high level in wild-type HCE-T cells and its supernatant, and in CNV patient tears. The proangiogenic functions of miR-1910-5p were demonstrated with the assays of cell migration, tube formation, and aortic ring. Moreover, miR-1910-5p significantly inhibited multimerin-2 expression by targeting its 3ʹ untranslated region and caused significant extracellular junctional defects in human umbilical vein endothelial cells. MiR-1910-5p antagomir could significantly increase multimerin-2 level and decrease vascular leakage, and ultimately inhibit CNV in a murine model. Conclusions Our results revealed a novel CXCR4-mediated mechanism and proved that targeting the miR-1910-5p/multimerin-2 pathway could be a promising therapeutic target for CNV.

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“…CD93 also played roles in apoptosis, phagocytosis, inflammation, and cell adhesion ( Nepomuceno et al, 1997 ; McGreal et al, 2002 ; Norsworthy et al, 2004 ). Interestingly, a key step during vascular maturation included the deposition of Multimerin-2, which acted not only as a substrate for pericyte adhesion but also as a central modifier of the expression pattern of important molecules regulating the crosstalk between ECs and pericytes and vascular stability ( Fejza et al, 2021 ). However, as we all know, multimerin-2 is a known CD93 ligand ( Galvagni et al, 2017 ; Khan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis

Zhang

Zheng

Ding

et al. 2022

Front. Cell Dev. Biol.

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Background: The clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1, and PD-L1 has revolutionized the treatment of cancer. However, the majority of patients do not derive clinical benefit. Further development is needed to optimize the approach of ICI therapy. Immunotherapy combined with other forms of treatment is a rising strategy for boosting antitumor responses. CD93 was found to sensitize tumors to immune-checkpoint blocker therapy after the blockade of its pathway. However, its role in immune and ICB therapy across pan-cancer has remained unexplored.Methods: In this study, we provide a comprehensive investigation of CD93 expression in a pan-cancer manner involving 33 cancer types. We evaluated the association of CD93 expression with prognosis, mismatch repair, tumor mutation burden, and microsatellite instability, immune checkpoints, tumor microenvironment, and immune using multiple online datasets, including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Tumor Immune Estimation Resource database, and Tumor Immune Single-cell Hub.Results: CD93 expression varied strongly among cancer types, and increased CD93 gene expression was associated with poor prognosis as well as higher immune factors in most cancer types. Additionally, the level of CD93 was significantly correlated with MMR, TMB, MSI, immune checkpoints, TME, and immune cell infiltration. Noticeably, our results mediated a strong positive contact between CD93 and CAFs, endothelial cells, myeloid dendritic cells, hematopoietic stem cells, mononuclear/macrophage subsets, and neutrophils while a negative correlation with Th1, MDSC, NK, and T-cell follicular helper in almost all cancers. Function analysis on CD93 revealed a link between itself and promoting cancers, inflammation, and angiogenesis.Conclusion: CD93 can function as a prognostic marker in various malignant tumors and is integral in TME and immune infiltration. Inhibition of the CD93 pathway may be a novel and promising strategy for immunotherapy in human cancer. Further explorations of the mechanisms of CD93 in the immune system may help improve cancer therapy methods.

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Multimerin-2 orchestrates the cross-talk between endothelial cells and pericytes: A mechanism to maintain vascular stability

Cited by 10 publications

References 65 publications

Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability

Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability

The CXCR4/miR-1910-5p/MMRN2 Axis Is Involved in Corneal Neovascularization by Affecting Vascular Permeability

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis

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