LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

Camillo, Chiara Di; Facchinello, Nicola; Villari, Giulia; Mana, Giulia; Gioelli, Noemi; Sandri, Chiara; Astone, Matteo; Tortarolo, Dora; Clapero, Fabiana; Gays, Dafne; Oberkersch, Roxana E; Arese, Marco; Tamagnone, Luca; Valdembri, Donatella; Santoro, Massimo; Serini, Guido

doi:10.1101/2020.04.28.065979

Cited by 4 publications

(4 citation statements)

References 81 publications

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“…Given the role of FLRT2 in modulating cortical migration during nervous system development, Akita et al proposed an analogous guidance function for FLRT2 in vascular development (Akita et al, 2016). FLRT2 is one of the primary ligands that binds and activates the adhesion G protein-coupled receptor LPHN2 , which acts as a repulsive guidance receptor that controls blood vessel structure and function in model systems (Camillo et al, 2021). FLRT2 has also been identified as an autoantigen, or cell-surface target, of anti-endothelial cell antibodies in the vascular systems of patients with systemic lupus erythematosus (Shirai et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

Singhal

Veturi

Dudek

et al. 2022

Preprint

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Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWAS). Standard GWAS are well-powered to interrogate additive models; however, new approaches are required to investigate other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected due to lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWAS excludes detection of sites in LD that may underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for associations between 23 common diseases and 5,625,845 epistatic SNP-SNP pairs (determined by Ohta’sDstatistics) in long-range LD (> 0.25cM). We identified five significant associations across five disease phenotypes that replicated in two large genotype-phenotype datasets (UK Biobank and eMERGE). The genes that were most likely involved in the replicated associations were 1) members of highly conserved gene families with complex roles in multiple pathways, 2) essential genes, and/or 3) associated in the literature with complex traits that display variable expressivity. These results support the highly pleiotropic and conserved nature of variants in long-range under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and may especially be driving factors in conditions with a wide range of phenotypic outcomes.SignificanceCurrent knowledge of genotype-phenotype relationships is largely contingent on traditional univariate approaches to genomic analysis. Yet substantial evidence supports non-additive modes of inheritance and regulation, such as epistasis, as being abundant across the genome. In this genome-wide study, we probe the biomolecular mechanisms underlying complex human diseases by testing the association of pairwise genetic interactions with disease occurrence in large-scale biobank data. Specifically, we tested intrachromosomal and interchrosomal long-range interactions between regions of the genome in high linkage disequilibrium, these regions are typically excluded from genomic analyses. The results from this study suggest that essential gene, members of highly conserved gene families, and phenotypes with variable expressivity, are particularly enriched with epistatic and pleiotropic activity.

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Section: Discussionmentioning

confidence: 99%

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

Singhal

Veturi

Dudek

et al. 2022

Preprint

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“…8A). ECM deposition is essential for mechanical support of vessels and guidance of cellular differentiation and functions ( 30 ). The ECM protein assembly and distribution in PHA/PEGDA-GDY scaffolds were similar to those of native vessels.…”

Section: Resultsmentioning

confidence: 99%

Amphiphilic and fatigue-resistant organohydrogels for small-diameter vascular grafts

Hou

Zhang

et al. 2022

Sci. Adv.

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Hydrogels are used in vascular tissue engineering because of their good biocompatibility. However, most natural hydrogels exhibit high swelling ratio, poor mechanical stability, and low durability, which are key limitations for wider applications. Amphiphilic and fatigue-resistant organohydrogels were fabricated here via the click chemical reaction of unsaturated functional microbial polyhydroxyalkanoates and polyethylene glycol diacrylate and a combination of two-dimensional material graphdiyne. These organohydrogels were maintained stable in body fluids over time, and their tensile moduli remained unchanged after more than 2000 cycles of cyclic stretching. The tubular scaffolds presented good biocompatibility and perfusion in vitro. After transplantation in vivo, the vascular grafts exhibited obvious cell infiltration and tissue regeneration, having a higher patency rate than the control group in 3 months. This fabrication method provides a strategy of improving and promoting the application of organohydrogels as implant materials for small-diameter vascular graft.

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“…Mice lacking homophilic Flrt2 binding specifically in endothelial cells (Cdh5-Cre ERT2+ Flrt2 flox/R186N+D188T ; referred to hereafter as Flrt2 iΔEC/ΔFF ) showed suppression of tumor growth, angiogenesis, and hemorrhaging, similar to those in Flrt2 iΔEC mice (Figure 8C-E, N-Q). It should be noted that the FLRT2-latrophilins interaction (17,37,38) could account for this phenotype, in addition to its homophilic binding. A metastatic model based on AXT cells also showed that tumors in Flrt2 iΔEC/ΔFF demonstrated markedly lower levels of intravasation and metastasis than those in control mice (Figure 8F-M, R, S), suggesting that homophilic binding of Flrt2 provides the inter-endothelial adhesion required for maintenance of abnormalized vessels.…”

Section: Homophilic Binding Of Flrt2 Constitutes Tumor-specific Inter-endothelial Adhesionmentioning

confidence: 96%

Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness

Ando¹,

Tai-Nagara²,

Kusumoto³

et al. 2022

Journal of Clinical Investigation

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Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans, and that its expression correlates negatively with long-term survival. Endothelial-specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed "oxygen-glucose uncoupling", which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the anti-tumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms non-canonical inter-endothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific inter-endothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.

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LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

Cited by 4 publications

References 81 publications

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

Amphiphilic and fatigue-resistant organohydrogels for small-diameter vascular grafts

Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness

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