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Dejana, Elisabetta
Publications (10 of 18) Show all publications
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
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
Malinverno, M., Corada, M., Ferrarini, L., Formicola, L., Marazzi, G., Sassoon, D. & Dejana, E. (2017). Peg3/PW1 Is a Marker of a Subset of Vessel Associated Endothelial Progenitors. Stem Cells, 35(5), 1328-1340
Open this publication in new window or tab >>Peg3/PW1 Is a Marker of a Subset of Vessel Associated Endothelial Progenitors
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2017 (English)In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 35, no 5, p. 1328-1340Article in journal (Refereed) Published
Abstract [en]

Vascular associated endothelial cell (ECs) progenitors are still poorly studied and their role in the newly forming vasculature at embryonic or postnatal stage remains elusive. In the present work, we first defined a set of genes highly expressed during embryo development and strongly downregulated in the adult mouse. In this group, we then concentrated on the progenitor cell marker Peg3/PW1. By in vivo staining of the vasculature we found that only a subset of cells coexpressed endothelial markers and PW1. These cells were quite abundant in the embryo vasculature but declined in number at postnatal and adult stages. Using a reporter mouse for PW1 expression, we have been able to isolate PW1-positive (PW1posECs) and negative endothelial cells (PW1negECs). PW1-positive cells were highly proliferative in comparison to PW1negECs and were able to form colonies when seeded at clonal dilution. Furthermore, by RNAseq analysis, PW1posECs expressed endothelial cell markers together with mesenchymal and stem cell markers. When challenged by endothelial growth factors in vitro, PW1posECs were able to proliferate more than PW1negECs and to efficiently form new vessels in vivo. Taken together these data identify a subset of vessel associated endothelial cells with characteristics of progenitor cells. Considering their high proliferative potential these cells may be of particular importance to design therapies to improve the perfusion of ischemic tissues or to promote vascular repair.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
Angiogenesis, Vascular associated endothelial progenitors, Peg3/PW1, Gene expression profiling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-322714 (URN)10.1002/stem.2566 (DOI)000400017200018 ()28090691 (PubMedID)
Available from: 2017-05-29 Created: 2017-05-29 Last updated: 2017-05-29Bibliographically approved
Chiang, I.-N. K., Fritzsche, M., Pichol-Thievend, C., Neal, A., Holmes, K., Lagendijk, A., . . . Francois, M. (2017). SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development. Development, 144(14), 2629-2639
Open this publication in new window or tab >>SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development
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2017 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 14, p. 2629-2639Article in journal (Refereed) Published
Abstract [en]

Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancerswere able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo. Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD, 2017
Keywords
Notch1, SoxF, Artery, Arterial enhancer, Endothelial cell, Transcriptional regulation, Zebrafish, Human, Mouse
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-331237 (URN)10.1242/dev.146241 (DOI)000405701000010 ()28619820 (PubMedID)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-10-16Bibliographically approved
Dejana, E., Hirschi, K. K. & Simons, M. (2017). The molecular basis of endothelial cell plasticity. Nature Communications, 8, Article ID 14361.
Open this publication in new window or tab >>The molecular basis of endothelial cell plasticity
2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14361Article, review/survey (Refereed) Published
Abstract [en]

The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-317094 (URN)10.1038/ncomms14361 (DOI)000393587100001 ()28181491 (PubMedID)
Funder
EU, European Research Council, 268870 317250 675619NIH (National Institute of Health), HL053793 P01 HL107205 HL128064 HL096360 EB017103
Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2017-11-29Bibliographically approved
Bravi, L., Malinverno, M., Pisati, F., Rudini, N., Cuttano, R., Pallini, R., . . . Lampugnani, M. G. (2016). Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition. Stroke, 47(3), 886-890
Open this publication in new window or tab >>Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition
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2016 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 47, no 3, p. 886-890Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy.

METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control.

RESULTS: We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad- and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones.

CONCLUSIONS: Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.

National Category
Basic Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-279206 (URN)10.1161/STROKEAHA.115.011867 (DOI)000371496200038 ()26839352 (PubMedID)
Funder
EU, European Research Council, 268870EU, European Research Council, 317250EU, European Research Council, 675619
Note

Dejana E and Lampugnani MG share the last authorship.

Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-01-10Bibliographically approved
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