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Miloudi, K., Oubaha, M., Menard, C., Dejda, A., Guber, V., Cagnone, G., . . . Sapieha, P. (2019). NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy. Proceedings of the National Academy of Sciences of the United States of America, 116(10), 4538-4547
Open this publication in new window or tab >>NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 10, p. 4538-4547Article in journal (Refereed) Published
Abstract [en]

Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from beta-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2019
Keywords
diabetic macular edema, diabetic retinopathy, NOTCH, JAG1, DLL4
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-379896 (URN)10.1073/pnas.1814711116 (DOI)000460242100088 ()30787185 (PubMedID)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Gomez-Escudero, J., Clemente, C., Garcia-Weber, D., Acin-Perez, R., Millan, J., Enriquez, J. A., . . . Arroyo, A. G. (2019). PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production. Scientific Reports, 9, Article ID 15022.
Open this publication in new window or tab >>PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15022Article in journal (Refereed) Published
Abstract [en]

Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-396701 (URN)10.1038/s41598-019-50866-x (DOI)000491226200005 ()31636306 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2019-11-08 Created: 2019-11-08 Last updated: 2019-11-08Bibliographically approved
Page, D. J., Thuret, R., Venkatraman, L., Takahashi, T., Bentley, K. & Herbert, S. P. (2019). Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis. Cell reports, 27(11), 3139-3151.e5
Open this publication in new window or tab >>Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, no 11, p. 3139-3151.e5Article in journal (Refereed) Published
Abstract [en]

Angiogenesis is driven by the coordinated collective branching of specialized leading "tip" and trailing "stalk" endothelial cells (ECs). While Notch-regulated negative feedback suppresses excessive tip selection, roles for positive feedback in EC identity decisions remain unexplored. Here, by integrating computational modeling with in vivo experimentation, we reveal that positive feedback critically modulates the magnitude, timing, and robustness of angiogenic responses. In silico modeling predicts that positivefeedback-mediated amplification of VEGF signaling generates an ultrasensitive bistable switch that underpins quick and robust tip-stalk decisions. In agreement, we define a positive-feedback loop exhibiting these properties in vivo, whereby Vegf-induced expression of the atypical tetraspanin, tm4sf18, amplifies Vegf signaling to dictate the speed and robustness of EC selection for angiogenesis. Consequently, tm4sf18 mutant zebrafish select fewer motile ECs and exhibit stunted hypocellular vessels with unstable tip identity that is severely perturbed by even subtle Vegfr attenuation. Hence, positive feedback spatiot-emporally shapes the angiogenic switch to ultimately modulate vascular network topology.

National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-388771 (URN)10.1016/j.celrep.2019.05.052 (DOI)000470993200005 ()31189101 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationWellcome trust, 095718/Z/11/Z
Available from: 2019-07-05 Created: 2019-07-05 Last updated: 2019-07-05Bibliographically approved
Laviña, B., Castro, M., Niaudet, C., Cruys, B., Álvarez-Aznar, A., Carmeliet, P., . . . Gängel, K. (2018). Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations. Development, 145(13), Article ID UNSP dev161182.
Open this publication in new window or tab >>Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations
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2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 13, article id UNSP dev161182Article in journal (Refereed) Published
Abstract [en]

Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

Keywords
Vascular malformations, Cdc42, Cell migration, Endothelial axial polarity, Angiogenesis, Proliferation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361537 (URN)10.1242/dev.161182 (DOI)000439224400008 ()29853619 (PubMedID)
Funder
Swedish Research Council, VR2015-00550EU, European Research Council, 2011-294556EU, European Research Council, EU-ERC269073Knut and Alice Wallenberg Foundation, 2012.0272EU, FP7, Seventh Framework Programme, 317250Swedish Cancer Society, CAN2015/771The Wenner-Gren Foundation
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2018-10-01Bibliographically approved
Bentley, K. & Chakravartula, S. (2017). The temporal basis of angiogenesis. Philosophical Transactions of the Royal Society of London. Biological Sciences, 372(1720), 1-11, Article ID 20150522.
Open this publication in new window or tab >>The temporal basis of angiogenesis
2017 (English)In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 372, no 1720, p. 1-11, article id 20150522Article in journal (Refereed) Published
Abstract [en]

The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time-based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated 'temporal regulators' have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that 'temporal adaptation' provides a novel account of organ/disease-specific vascular morphology and reveals 'timing' as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a 'temporal adaptation' perspective in vascular biology, and indeed other areas of biology where timing remains elusive. This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.

Keywords
time, dynamics, morphogenesis, adaptation, active perception, vascular
National Category
Medical Genetics Developmental Biology Cell and Molecular Biology Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-321167 (URN)10.1098/rstb.2015.0522 (DOI)000397882500008 ()
Funder
Knut and Alice Wallenberg Foundation
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-01-13Bibliographically approved
Costa, G., Harrington, K. I., Lovegrove, H. E., Page, D. J., Chakravartula, S., Bentley, K. & Herbert, S. P. (2016). Asymmetric division coordinates collective cell migration in angiogenesis. Nature Cell Biology, 18(12), 1292-+
Open this publication in new window or tab >>Asymmetric division coordinates collective cell migration in angiogenesis
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2016 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 18, no 12, p. 1292-+Article in journal (Refereed) Published
Abstract [en]

The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-312061 (URN)10.1038/ncb3443 (DOI)000389134600007 ()27870831 (PubMedID)
Funder
NIH (National Institute of Health), T32 HL07893
Available from: 2017-01-04 Created: 2017-01-04 Last updated: 2018-01-13Bibliographically approved
Venkatraman, L., Regan, E. R. & Bentley, K. (2016). Time to Decide?: Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis. PLoS ONE, 11(11), Article ID e0166489.
Open this publication in new window or tab >>Time to Decide?: Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166489Article in journal (Refereed) Published
Abstract [en]

Angiogenesis is a highly dynamic morphogenesis process; however, surprisingly little is known about the timing of the different molecular processes involved. Although the role of the VEGF-notch-DLL4 signaling pathway has been established as essential for tip/stalk cell competition during sprouting, the speed and dynamic properties of the underlying process at the individual cell level has not been fully elucidated. In this study, using mathematical modeling we investigate how specific, biologically meaningful, local conditions around and within an individual cell can influence their unique tip/stalk phenotype switching kinetics. To this end we constructed an ordinary differential equation model of VEGF-notch-DLL4 signaling in a system of two, coupled endothelial cells (EC). Our studies reveal that at any given point in an angiogenic vessel the time it takes a cell to decide to take on a tip or stalk phenotype may be drastically different, and this asynchrony of tip/stalk cell decisions along vessels itself acts to speed up later competitions. We unexpectedly uncover intermediate "partial" yet stable states lying between the tip and stalk cell fates, and identify that internal cellular factors, such as NAD-dependent deacetylase sirtuin-1 (Sirt1) and Lunatic fringe 1 (Lfng1), can specifically determine the length of time a cell spends in these newly identified partial tip/stalk states. Importantly, the model predicts that these partial EC states can arise during normal angiogenesis, in particular during cell rearrangement in sprouts, providing a novel two-stage mechanism for rapid adaptive behavior to the cells highly dynamic environment. Overall, this study demonstrates that different factors (both internal and external to EC) can be used to modulate the speed of tip/stalk decisions, opening up new opportunities and challenges for future biological experiments and therapeutic targeting to manipulate vascular network topology, and our basic understanding of developmental/pathological angiogenesis.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-312090 (URN)10.1371/journal.pone.0166489 (DOI)000387794600070 ()
Available from: 2017-02-03 Created: 2017-01-04 Last updated: 2018-01-13Bibliographically approved
Li, X., Padhan, N., Sjöström, E. O., Roche, F. P., Testini, C., Honkura, N., . . . Claesson-Welsh, L. (2016). VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications, 7, Article ID 11017.
Open this publication in new window or tab >>VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed) Published
Abstract [en]

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-288617 (URN)10.1038/ncomms11017 (DOI)000372721400001 ()27005951 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, 294556 BBBARRIERWenner-Gren Foundations
Available from: 2016-05-11 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
Laviña, B., Castro, M., Niaudet, C., Bert, C., Peter, C., Bentley, K., . . . Gängel, K.Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformations.
Open this publication in new window or tab >>Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformations
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(English)Manuscript (preprint) (Other academic)
Keywords
Vascular malformations, Cdc42, cell migration, planar-cell-polarity, angiogenesis, proliferation
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-347774 (URN)
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-10-01Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9391-659x

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