{"id":15353,"date":"2026-05-21T13:11:13","date_gmt":"2026-05-21T13:11:13","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/rianne-schoon\/"},"modified":"2026-05-21T13:11:30","modified_gmt":"2026-05-21T13:11:30","slug":"rianne-schoon","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/rianne-schoon\/","title":{"rendered":"Rianne Schoon"},"content":{"rendered":"","protected":true},"excerpt":{"rendered":"","protected":true},"author":7,"featured_media":15354,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-15353","us_portfolio","type-us_portfolio","status-publish","post-password-required","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Building bridges","samenvatting":"Het onvolledige begrip van welke eiwitten VE-cadherine reguleren vormde de motivatie voor het onderzoek in dit proefschrift. In dit promotieproject hebben we getracht te identificeren en te karakteriseren welke eiwitten binden aan VE-cadherine en hoe deze interacties bijdragen aan de vasculaire functie. Wij hypothetiseerden dat VE-cadherine deelneemt aan gedefinieerde eiwitassociaties en dat partners kunnen veranderen afhankelijk van de biologische context. Met een combinatie van biochemische experimenten, mechanobiologische benaderingen en beeldvorming met hoge spatiotemporele resolutie, hebben we nieuwe VE-cadherine-bindende partners ge\u00efdentificeerd: ARVCF, KEAP1, ARHGAP23 en NGLY1. Verschillende van deze doelwitten werden verder bestudeerd op hun invloed op VE-cadherine en de adherens junctie (AJ). Daarnaast hebben we de rol onderzocht van de extracellulaire adhesie van VE-cadherine aan immuuncellen, en de functie van een eiwit dat VE-cadherine stabiliseert tijdens de vorming van bloedvaten gedurende de ontwikkeling. Gezamenlijk biedt dit proefschrift nieuwe inzichten die helpen verklaren hoe endotheliale juncties worden gereguleerd tijdens processen zoals collectieve celmigratie, leukocyt-transmigratie en mechanotransductie.\n\nIn Hoofdstuk 1 wordt een algemeen overzicht van bloedvaten gegeven. VE-cadherine wordt ge\u00efntroduceerd als een centrale moleculaire brug die cel-cel-adhesie medieert voor endotheliale en vasculaire integriteit. De moleculaire organisatie van het AJ-complex en de regulatiemechanismen worden besproken in de context van vasculaire integriteit.\n\nHoofdstuk 2 presenteert de experimentele ontdekking en karakterisering van nieuwe VE-cadherine-bindende eiwitten via proteomics. We presenteren vier nieuwe interactoren: ARVCF, KEAP1, ARHGAP23 en NGLY1. ARVCF wordt in detail bestudeerd, waarbij het mechanisme van associatie met VE-cadherine en de relevantie voor junctierijping en barri\u00e8restabiliteit wordt aangetoond.\n\nHoofdstuk 3 gaat verder met de analyse van de nieuw ontdekte eiwitten ARHGAP23, PKP4 en KEAP1 en hun rol bij endotheliale celverbindingen.\n\nHoofdstuk 4 richt zich op het extracellulaire domein van VE-cadherine, specifiek op twee RGD-motieven. Uit experimenten bleek dat deze motieven niet nodig zijn voor junctievorming, barri\u00e8re-integriteit of leukocytenpassage.\n\nHoofdstuk 5 onderzoekt hoe vinculine bijdraagt aan de endotheliale functie tijdens de ontwikkeling van bloedvaten. Met behulp van celkweek en een zebravismodellering laten we zien dat vinculine stabiele cel-celcontacten ondersteunt en vasculaire lekkage voorkomt.\n\nHoofdstuk 6 biedt een breder perspectief op mechanische regulatie tijdens inflammatie, met name hoe T-cellen de endotheliale membranen en junctiestructuren be\u00efnvloeden tijdens hun reis van de circulatie naar het weefsel.\n\nHoofdstuk 7 vat de bevindingen samen en plaatst deze in de bredere context van vasculaire biologie en ziekte. Gezamenlijk heeft dit proefschrift nieuwe inzichten gebracht, hoewel er nog veel innovatieve concepten te onderzoeken blijven.","summary":"The incomplete understanding of which proteins regulate VE-cadherin motivated the research presented in this thesis. In this PhD project, we set out to identify and characterize which proteins bind to VE-cadherin and how these interactions contribute to vascular function. We hypothesized that VE-cadherin engages in defined protein associations and that partners may change depending on the biological context. Using a combination of biochemical experiments, mechanobiological approaches, and high spatiotemporal resolution imaging, we identified new VE-cadherin-binding partners: ARVCF, KEAP1, ARHGAP23, and NGLY1. Several of these targets were further studied for their influence on VE-cadherin and the AJ. In addition, we investigated the role of VE-cadherin extracellular adhesion to immune cells, and the function of a protein that stabilizes VE-cadherin during blood vessel formation in development. Together, this thesis presents new insights that help explain how endothelial junctions are regulated during processes such as collective cell migration, leukocyte transmigration, and mechanotransduction.\n\nIn Chapter 1 a general overview of blood vessels was provided. VE-cadherin is introduced as a central molecular bridge that mediates cell-to-cell adhesion for endothelial and vascular integrity. The molecular organization of the AJ complex and its regulatory mechanisms are then discussed in the context of vascular integrity. Together, this chapter provides a foundation for understanding how VE-cadherin acts as a signaling platform at endothelial junctions and sets the stage for the novel interactors studied in the following experimental chapters.\n\nChapter 2 presents the experimental discovery and characterization of novel VE-cadherin-binding proteins. We used proteomics to uncover a core VE-cadherin interactome that includes several known junctional components and we present four novel interactors of VE-cadherin: ARVCF, KEAP1, ARHGAP23, and NGLY1. One of these proteins, ARVCF, is studied in further detail in this chapter: we unravel the molecular mechanism by which ARVCF associates with a distinct pool of VE-cadherin proteins and demonstrate its functional relevance for junction maturation, endothelial barrier stability, and collective cell migration. These findings expand our understanding of the VE-cadherin complex and introduce a new layer of regulation at the junctions.\n\nChapter 3 continues the analysis of the newly discovered VE-cadherin-binding proteins identified in chapter 2. We dive deeper into VE-cadherin regulation by exploring the roles of ARHGAP23, PKP4, and KEAP1 in endothelial cell connections. Although these proteins were less amenable to in-depth mechanistic studies, the performed experiments revealed that these proteins do contribute to the stability and organization of VE-cadherin-based cell-cell contacts. Together with the previous chapter, these findings provide complementary insights into the network of proteins, and their function, associated with the VE-cadherin complex.\n\nChapter 4 shifts the focus from intracellular regulators of VE-cadherin to its extracellular domain. Sticking outside of the endothelial cell membrane, this part of the protein contains two so-called RGD motifs, which are well-known integrin-binding sequences mediating adhesion, but their importance had never been studied on VE-cadherin. In our experiments we made non-functional variants and investigated their effects on junction formation, barrier integrity, and leukocyte passage. We found that the RGD motifs are not needed for any of these key endothelial cell functions, effectively resolving an open question and helping to refine future research to focus on the most functionally relevant regions of VE-cadherin.\n\nChapter 5 continues on the role of force sensitive proteins in maintaining vascular integrity. In this chapter, we investigate how vinculin, a protein that does not directly bind VE-cadherin but is recruited to junctions under mechanical tension, contributes to endothelial function during blood vessel development. By using both cell culture and a zebrafish model, we show that vinculin supports stable endothelial cell-cell contacts and helps prevent vascular leakage in newly forming vessels. These findings highlight the importance of mechanical reinforcement at adherens junctions and add a developmental perspective to the regulation of endothelial barrier function.\n\nChapter 6 reviews a broader perspective on the theme of mechanical regulation at endothelial adherens junctions, exploring how endothelial cells respond to mechanical cues during inflammation, particularly in the context of immune cell interactions. Quantitative research is presented on how T-cells, an important immune cell type, engage with and influence endothelial membranes and junctional structures during their journey from circulation, through the junctions, into the tissue, and how mechanotransduction pathways and proteins shape this process. By examining current concepts and molecular players, this chapter offers an integrated view of the dynamic mechanical crosstalk between immune cells and the vascular wall.\n\nChapter 7 summarizes our findings in this thesis and places them in the broader context of the vascular biology and disease field. Altogether, this thesis has brought insight, although there are still plenty innovative ideas and concepts to be explored, experimented, and discussed.","auteur":"Rianne Schoon","auteur_slug":"rianne-schoon","publicatiedatum":"1 juli 2026","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/rianneschoon?iframe=true","url_download_pdf":"https:\/\/ebook.proefschriftmaken.nl\/download\/46f06a17-0ecb-477f-b78a-fdc4acc40a43\/optimized","url_epub":"","ordernummer":"19057","isbn":"978-94-6534-453-9","doi_nummer":"","naam_universiteit":"Universiteit van Amsterdam","afbeeldingen":15355,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit van Amsterdam","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/15353","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=15353"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/15353\/revisions"}],"predecessor-version":[{"id":15356,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/15353\/revisions\/15356"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/15354"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=15353"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=15353"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}