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Dejana, Elisabetta
Publications (10 of 22) Show all publications
Lugano, R., Vemuri, K., Yu, D., Bergqvist, M., Smits, A., Essand, M., . . . Dimberg, A. (2018). CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.. Journal of Clinical Investigation, 128(8), 3280-3297
Open this publication in new window or tab >>CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed) Published
Abstract [en]

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

Keywords
Brain cancer, Fibronectin, Oncology, Vascular Biology, endothelial cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350902 (URN)10.1172/JCI97459 (DOI)000440461500015 ()29763414 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/832Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, CAN 2015/1216Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-11-08Bibliographically approved
Dejana, E. & Lampugnani, M. G. (2018). Endothelial cell transitions. Science, 362(6416), 746-747
Open this publication in new window or tab >>Endothelial cell transitions
2018 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 362, no 6416, p. 746-747Article in journal, Editorial material (Other academic) Published
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-373532 (URN)10.1126/science.aas9432 (DOI)000450488500026 ()30442789 (PubMedID)
Available from: 2019-01-21 Created: 2019-01-21 Last updated: 2019-01-21Bibliographically approved
Krispin, S., Stratman, A. N., Melick, C. H., Stan, R. V., Malinverno, M., Gleklen, J., . . . Weinstein, B. M. (2018). Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling. Arteriosclerosis, Thrombosis and Vascular Biology, 38(2), 353-362
Open this publication in new window or tab >>Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling
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2018 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 2, p. 353-362Article in journal (Refereed) Published
Abstract [en]

Objective - The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High vascular endothelial growth factor activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of prostabilization signals are still mostly unknown. Bone morphogenetic protein receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for growth differentiation factor 6 (GDF6; bone morphogenetic protein 13) in vascular integrity although GDF6's mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization.

Approach and Results - We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured human umbilical vein endothelial cells in vitro. We report that GDF6 promotes vascular integrity by counteracting vascular endothelial growth factor activity. GDF6-deficient endothelium has increased vascular endothelial growth factor signaling, increased vascular endothelial-cadherin Y658 phosphorylation, vascular endothelial-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak.

Conclusions - Our results suggest that GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2018
Keywords
bone morphogenetic protein receptors, cadherins, growth differentiation factor 6, human umbilical vein endothelial cells, vascular endothelial growth factor A
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-343787 (URN)10.1161/ATVBAHA.117.309571 (DOI)000423201600012 ()29284606 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved
Krispin, S., Stratman, A. N., Melick, C. H., Stan, R. V., Malinverno, M., Gleklen, J., . . . Weinstein, B. M. (2018). Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling. Arteriosclerosis, Thrombosis and Vascular Biology, 38(2), 353-362
Open this publication in new window or tab >>Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling
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2018 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 2, p. 353-362Article in journal (Refereed) Published
Abstract [en]

Objective

The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High vascular endothelial growth factor activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of prostabilization signals are still mostly unknown. Bone morphogenetic protein receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for growth differentiation factor 6 (GDF6; bone morphogenetic protein 13) in vascular integrity although GDF6's mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization.

Approach and Results

We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured human umbilical vein endothelial cells in vitro. We report that GDF6 promotes vascular integrity by counteracting vascular endothelial growth factor activity. GDF6-deficient endothelium has increased vascular endothelial growth factor signaling, increased vascular endothelial-cadherin Y658 phosphorylation, vascular endothelial-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak.

Conclusions

Our results suggest that GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans.

Keywords
bone morphogenetic protein receptors, cadherins, growth differentiation factor 6, human umbilical vein endothelial cells, vascular endothelial growth factor A
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-343654 (URN)10.1161/ATVBAHA.117.309571 (DOI)000423201600012 ()
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-05-09Bibliographically approved
Hirschi, K. K. & Dejana, E. (2018). Resident Endothelial Progenitors Make Themselves at Home. Cell Stem Cell, 23(2), 153-155
Open this publication in new window or tab >>Resident Endothelial Progenitors Make Themselves at Home
2018 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 23, no 2, p. 153-155Article in journal, Editorial material (Other academic) Published
Abstract [en]

Vascular endothelial cells adapt to their microenvironment and physiological demands to perform many essential functions. Recent studies (McDonald et al., 2018; Wakabayashi et al., 2018) suggest that quiescent endothelial stem/progenitor cells reside within blood vessels and are activated in response to injury, suggesting they can be harnessed for therapeutic applications.

Place, publisher, year, edition, pages
CELL PRESS, 2018
National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366307 (URN)10.1016/j.stem.2018.07.014 (DOI)000440583900003 ()30075124 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2018-11-20Bibliographically approved
Lampugnani, M. G., Dejana, E. & Giampietro, C. (2018). Vascular Endothelial (VE)-Cadherin, Endothelial Adherens Junctions, and Vascular Disease. Cold Spring Harbor Perspectives in Biology, 10(10), Article ID a029322.
Open this publication in new window or tab >>Vascular Endothelial (VE)-Cadherin, Endothelial Adherens Junctions, and Vascular Disease
2018 (English)In: Cold Spring Harbor Perspectives in Biology, ISSN 1943-0264, E-ISSN 1943-0264, Vol. 10, no 10, article id a029322Article in journal (Refereed) Published
Abstract [en]

Endothelial cell - cell adherens junctions (AJs) supervise fundamental vascular functions, such as the control of permeability and transmigration of circulating leukocytes, and the maintenance of existing vessels and formation of new ones. These processes are often dysregulated in pathologies. However, the evidence that links dysfunction of endothelial AJs to human pathologies is mostly correlative. In this review, we present an update of the molecular organization of AJ complexes in endothelial cells (ECs) that is mainly based on observations from experimental models. Furthermore, we report in detail on a human pathology, cerebral cavernous malformation (CCM), which is initiated by loss-of-function mutations in the genes that encode the three cytoplasmic components of AJs (CCM1, CCM2, and CCM3). At present, these represent a unique example of mutations in components of endothelial AJs that cause human disease. We describe also how studies into the defects of AJs in CCM are shedding light on the crucial regulatory mechanisms and signaling activities of these endothelial structures. Although these observations are specific for CCM, they support the concept that dysfunction of endothelial AJs can directly contribute to human pathologies.

Place, publisher, year, edition, pages
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368100 (URN)10.1101/cshperspect.a029322 (DOI)000446016200007 ()28851747 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved
Morini, M. F., Giampietro, C., Corada, M., Pisati, F., Lavarone, E., Cunha, S. I., . . . Taddei, A. (2018). VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression. Circulation Research, 122(2), 231-245
Open this publication in new window or tab >>VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression
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2018 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 122, no 2, p. 231-245Article in journal (Refereed) Published
Abstract [en]

Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability.

Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization.

Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and beta-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/beta-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP.

Conclusions: These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2018
Keywords
blood vessels, cadherin, cell differentiation, endothelial cells, polycomb-group proteins
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-349850 (URN)10.1161/CIRCRESAHA.117.312392 (DOI)000425967600011 ()29233846 (PubMedID)
Funder
Wellcome trust, FC001057EU, European Research Council, 742922Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2018-05-03Bibliographically approved
Cunha, S. I., Magnusson, P., Dejana, E. & Lampugnani, M. G. (2017). Deregulated TGF-beta/BMP Signaling in Vascular Malformations. Circulation Research, 121(8), 981-999
Open this publication in new window or tab >>Deregulated TGF-beta/BMP Signaling in Vascular Malformations
2017 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, no 8, p. 981-999Article, review/survey (Refereed) Published
Abstract [en]

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-beta/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-beta/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-beta/BMP receptor complex and the second to increased signaling sensitivity to TGF-beta/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

Keywords
cell differentiation, mutation, signal transduction, transforming growth factors, vascular malformations
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-346839 (URN)10.1161/CIRCRESAHA.117.309930 (DOI)000412807600019 ()28963191 (PubMedID)
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-03-28Bibliographically approved
Lampugnani, M. G., Malinverno, M., Dejana, E. & Rudini, N. (2017). Endothelial cell disease: emerging knowledge from cerebral cavernous malformations. Current opinion in hematology, 24(3), 256-264
Open this publication in new window or tab >>Endothelial cell disease: emerging knowledge from cerebral cavernous malformations
2017 (English)In: Current opinion in hematology, ISSN 1065-6251, E-ISSN 1531-7048, Vol. 24, no 3, p. 256-264Article, review/survey (Refereed) Published
Abstract [en]

Purpose of review Endothelial cells dysfunctions are crucial determinants of several human diseases. We review here the most recent reports on endothelial cell defects in cerebral cavernous malformations (CCMs), particularly focusing on adherens junctions. CCM is a vascular disease that affects specifically the venous microvessels of the central nervous system and which is caused by loss-of-function mutation in any one of the three CCM genes (CCM1, 2 or 3) in endothelial cells. The phenotypic result of these mutations are focal vascular malformations that are permeable and fragile causing neurological symptoms and occasionally haemorrhagic stroke. Recent findings CCM is still an incurable disease, as no pharmacological treatment is available, besides surgery. The definition of the molecular alterations ensuing loss of function mutation of CCM genes is contributing to orientate the testing of targeted pharmacological tools Several signalling pathways are altered in the three genotypes in a similar way and concur in the acquisition of mesenchymal markers in endothelial cells. However, also genotype-specific defects are reported, in particular for the CCM1 and CCM3 mutation. Summary Besides the specific CCM disease, the characterization of endothelial alterations in CCM has the potentiality to shed light on basic molecular regulations as the acquisition and maintenance of organ and vascular site specificity of endothelial cells.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
Keywords
angiogenesis, cerebral cavernous malformation, endothelial cells, endothelial-to-mesenchymal transition
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-331026 (URN)10.1097/MOH.0000000000000338 (DOI)000400929700015 ()28212190 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2017-10-10 Created: 2017-10-10 Last updated: 2017-10-10
Erba, B. G., Gruppi, C., Corada, M., Pisati, F., Rosti, V., Bartalucci, N., . . . Dejana, E. (2017). Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis. American Journal of Pathology, 187(8), 1879-1892
Open this publication in new window or tab >>Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis
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2017 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 8, p. 1879-1892Article in journal (Refereed) Published
Abstract [en]

Primary myelofibrosis is characterized by the development of fibrosis in the bone marrow that contributes to ineffective hematopoiesis. Bone marrow fibrosis is the result of a complex and not yet fully understood interaction among megakaryocytes, myeloid cells, fibroblasts, and endothelial cells. Here, we report that >30% of the endothelial cells in the small vessels of the bone marrow and spleen of patients with primary myelofibrosis have a mesenchymal phenotype, which is suggestive of the process known as endothelial-to-mesenchymal transition (EndMT). EndMT can be reproduced in vitro by incubation of cultured endothelial progenitor cells or spleen-derived endothelial cells with inflammatory cytokines. Megakaryocytes appear to be implicated in this process, because EndMT mainly occurs in the microvessels close to these cells, and because megakaryocyte-derived supernatant fluid can reproduce the EndMT switch in vitro. Furthermore, EndMT is an early event in a JAK2-V617F knock-in mouse model of primary myelofibrosis. Overall, these data show for the first time that microvascular endothelial cells in the bone marrow and spleen of patients with primary myelofibrosis show functional and morphologic changes that are associated to the mesenchymal phenotype.

National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-332932 (URN)10.1016/j.ajpath.2017.04.006 (DOI)000406080300018 ()28728747 (PubMedID)
Funder
EU, European Research Council, 268870Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2018-01-13Bibliographically approved
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