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Article ; Online: Cellular Origin of Sporadic CCMs.

Betsholtz, Christer / Gaengel, Konstantin / Mäkinen, Taija

2022 Volume 386, Issue 13, Page(s) 1291

MeSH term(s)	Humans ; Intellectual Disability ; Micrognathism ; Ribs
Language	English
Publishing date	2022-03-29
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc2117812
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Article ; Online: Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage.

Vázquez-Liébanas, Elisa / Mocci, Giuseppe / Li, Weihan / Laviña, Bàrbara / Reddy, Avril / O'Connor, Claire / Hudson, Natalie / Elbeck, Zaher / Nikoloudis, Ioannis / Gaengel, Konstantin / Vanlandewijck, Michael / Campbell, Matthew / Betsholtz, Christer / Mäe, Maarja Andaloussi

Cell reports

2024 Volume 43, Issue 3, Page(s) 113911

Abstract: Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the ... ...

Abstract	Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the brain. To study the consequences of CLDN5 loss in the mature brain, we induced mosaic endothelial-specific Cldn5 gene ablation in adult mice (Cldn5
MeSH term(s)	Animals ; Mice ; Biological Transport ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Claudin-5/genetics ; Claudin-5/metabolism ; Endothelial Cells/metabolism
Chemical Substances	Claudin-5 ; Cldn5 protein, mouse
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.113911
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Article ; Online: New imaging methods and tools to study vascular biology.

Laviña, Bàrbara / Gaengel, Konstantin

Current opinion in hematology

2015 Volume 22, Issue 3, Page(s) 258–266

Abstract: Purpose of review: Throughout history, development of novel microscopy techniques has been of fundamental importance to advance the vascular biology field.This review offers a concise summary of the most recently developed imaging techniques and ... ...

Abstract	Purpose of review: Throughout history, development of novel microscopy techniques has been of fundamental importance to advance the vascular biology field.This review offers a concise summary of the most recently developed imaging techniques and discusses how they can be applied to vascular biology. In addition, we reflect upon the most important fluorescent reporters for vascular research that are currently available. Recent findings: Recent advances in light sheet-based imaging techniques now offer the ability to live image the vascular system in whole organs or even in whole animals during development and in pathological conditions with a satisfactory spatial and temporal resolution. Conversely, super resolution microscopy now allows studying cellular processes at a near-molecular resolution. Summary: Major recent improvements in a number of imaging techniques now allow study of vascular biology in ways that could not be considered previously. Researchers now have well-developed tools to specifically examine the dynamic nature of vascular development during angiogenic sprouting, remodeling and regression as well as the vascular responses in disease situations in vivo. In addition, open questions in endothelial and lymphatic cell biology that require subcellular resolution such as actin dynamics, junctional complex formation and stability, vascular permeability and receptor trafficking can now be approached with high resolution.
MeSH term(s)	Blood Vessels/metabolism ; Humans ; Image Processing, Computer-Assisted/methods
Language	English
Publishing date	2015-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000141
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Article ; Online: VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function.

Álvarez-Aznar, Alberto / Muhl, Lars / Gaengel, Konstantin

Current topics in developmental biology

2017 Volume 123, Page(s) 433–482

Abstract: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are key regulators of vascular development in vertebrates. Their activation is regulated through a family of secreted glycoproteins, the vascular endothelial growth factors (VEGFs). ... ...

Abstract	Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are key regulators of vascular development in vertebrates. Their activation is regulated through a family of secreted glycoproteins, the vascular endothelial growth factors (VEGFs). Expression, proteolytic processing, and diffusion range of VEGF proteins need to be tightly regulated, due to their crucial roles in development. While some VEGFs form concentration gradients across developing tissues and act as morphogenes, others function as inhibitors of receptor activation and downstream signaling. Ligand-induced receptor dimerization leads to activation of the intrinsic tyrosine kinase activity, which results in autophosphorylation of the receptors and in turn triggers the recruitment of interacting proteins as well as the initiation of downstream signaling. Although many biochemical details of VEGFR signaling have been revealed, the in vivo relevance of certain signaling aspects still remains to be demonstrated. Here, we highlight basic principles of VEGFR signaling and discuss its crucial role during development of the vascular system in mammals.
MeSH term(s)	Animals ; Blood Vessels/physiology ; Evolution, Molecular ; Humans ; Ligands ; Neuropilins/metabolism ; Receptors, Vascular Endothelial Growth Factor/chemistry ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Signal Transduction
Chemical Substances	Ligands ; Neuropilins ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1557-8933 ; 0070-2153
ISSN (online)	1557-8933
ISSN	0070-2153
DOI	10.1016/bs.ctdb.2016.10.001
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Article ; Online: Integrins are required for synchronous ommatidial rotation in the Drosophila eye linking planar cell polarity signalling to the extracellular matrix.

Thuveson, Maria / Gaengel, Konstantin / Collu, Giovanna M / Chin, Mei-Ling / Singh, Jaskirat / Mlodzik, Marek

Open biology

2019 Volume 9, Issue 8, Page(s) 190148

Abstract: Integrins mediate the anchorage between cells and their environment, the extracellular matrix (ECM), and form transmembrane links between the ECM and the cytoskeleton, a conserved feature throughout development and morphogenesis of epithelial organs. ... ...

Abstract	Integrins mediate the anchorage between cells and their environment, the extracellular matrix (ECM), and form transmembrane links between the ECM and the cytoskeleton, a conserved feature throughout development and morphogenesis of epithelial organs. Here, we demonstrate that integrins and components of the ECM are required during the planar cell polarity (PCP) signalling-regulated cell movement of ommatidial rotation in the Drosophila eye. The loss-of-function mutations of integrins or ECM components cause defects in rotation, with mutant clusters rotating asynchronously compared to wild-type clusters. Initially, mutant clusters tend to rotate faster, and at later stages they fail to be synchronous with their neighbours, leading to aberrant rotation angles and resulting in a disorganized ommatidial arrangement in adult eyes. We further demonstrate that integrin localization changes dynamically during the rotation process. Our data suggest that core Frizzled/PCP factors, acting through RhoA and Rho kinase, regulate the function/activity of integrins and that integrins thus contribute to the complex interaction network of PCP signalling, cell adhesion and cytoskeletal elements required for a precise and synchronous 90° rotation movement.
MeSH term(s)	Animals ; Body Patterning ; Cell Polarity ; Drosophila/embryology ; Drosophila/physiology ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Extracellular Matrix/metabolism ; Eye/cytology ; Eye/embryology ; Eye/metabolism ; Gene Deletion ; Gene Expression Regulation, Developmental ; Immunohistochemistry ; Integrins/genetics ; Integrins/metabolism ; Models, Biological ; Mutation ; Protein Transport ; Signal Transduction
Chemical Substances	Drosophila Proteins ; Integrins
Language	English
Publishing date	2019-08-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.190148
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Article ; Online: Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow.

Orlich, Michael M / Diéguez-Hurtado, Rodrigo / Muehlfriedel, Regine / Sothilingam, Vithiyanjali / Wolburg, Hartwig / Oender, Cansu Ebru / Woelffing, Pascal / Betsholtz, Christer / Gaengel, Konstantin / Seeliger, Mathias / Adams, Ralf H / Nordheim, Alfred

Circulation research

2022 Volume 131, Issue 4, Page(s) 308–327

Abstract: Background: Pericytes and vascular smooth muscle cells, collectively known as mural cells, are recruited through PDGFB (platelet-derived growth factor B)-PDGFRB (platelet-derived growth factor receptor beta) signaling. MCs are essential for vascular ... ...

Abstract	Background: Pericytes and vascular smooth muscle cells, collectively known as mural cells, are recruited through PDGFB (platelet-derived growth factor B)-PDGFRB (platelet-derived growth factor receptor beta) signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions. Here, we characterize the role of the transcription factor SRF (serum response factor) in MCs and study its function in developmental and pathological contexts. Methods: We generated a mouse model of MC-specific inducible Results: By postnatal day 6, pericytes lacking SRF were morphologically abnormal and failed to properly comigrate with angiogenic sprouts. As a consequence, pericyte-deficient vessels at the retinal sprouting front became dilated and leaky. By postnatal day 12, also the vascular smooth muscle cells had lost SRF, which coincided with the formation of pathological arteriovenous shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF (myocardin-related transcription factor) cofactors. We further show that MRTF-SRF signaling promotes pathological pericyte activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging, and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone. Conclusions: SRF is crucial for distinct functions in pericytes and vascular smooth muscle cells. SRF directs pericyte migration downstream of PDGFRB signaling and mediates pathological pericyte activation during ischemic retinopathy. In vascular smooth muscle cells, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of arteriovenous shunts. These essential roles in physiological and pathological contexts provide a rationale for novel therapeutic approaches through targeting SRF activity in MCs.
MeSH term(s)	Animals ; Mice ; Pericytes/metabolism ; Proto-Oncogene Proteins c-sis/metabolism ; RNA/metabolism ; Receptor, Platelet-Derived Growth Factor beta/genetics ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Retinal Diseases/metabolism ; Serum Response Factor/genetics ; Serum Response Factor/metabolism
Chemical Substances	Proto-Oncogene Proteins c-sis ; Serum Response Factor ; Srf protein, mouse ; RNA (63231-63-0) ; Receptor, Platelet-Derived Growth Factor beta (EC 2.7.10.1)
Language	English
Publishing date	2022-07-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.122.321109
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Ui IV Zs.70: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Ui IV Zs.60: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Endocytosis regulates VEGF signalling during angiogenesis.

Gaengel, Konstantin / Betsholtz, Christer

Nature cell biology

2011 Volume 15, Issue 3, Page(s) 233–235

Abstract: Endocytosis has proved to be a versatile mechanism regulating diverse cellular processes, ranging from nutrient uptake to intracellular signal transduction. New work reinforces the importance of endocytosis for VEGF receptor signalling and angiogenesis ... ...

Abstract	Endocytosis has proved to be a versatile mechanism regulating diverse cellular processes, ranging from nutrient uptake to intracellular signal transduction. New work reinforces the importance of endocytosis for VEGF receptor signalling and angiogenesis in the developing eye, and describes a mechanism for its differential regulation in angiogenic versus quiescent endothelial cells.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Apoptosis Regulatory Proteins ; Cell Adhesion Molecules/metabolism ; Cell Cycle Proteins ; Endocytosis/physiology ; Endothelium, Vascular/cytology ; Ephrin-B2/metabolism ; Female ; Humans ; Male ; Neovascularization, Physiologic ; Protein Kinase C/metabolism ; Receptors, Vascular Endothelial Growth Factor/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Apoptosis Regulatory Proteins ; Cell Adhesion Molecules ; Cell Cycle Proteins ; Dab2 protein, mouse ; Ephrin-B2 ; Pard3 protein, mouse ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; PKC-3 protein (EC 2.7.11.13) ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2011-11-04
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb2705
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Zs.A 5169: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 12: Show issues

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Article ; Online: Incongruence between transcriptional and vascular pathophysiological cell states.

Nature cardiovascular research

2023 Volume 2, Page(s) 2023530–2023549

Abstract: The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling ... ...

Abstract	The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTOR, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.
Language	English
Publishing date	2023-08-29
Publishing country	England
Document type	Journal Article
ISSN	2731-0590
ISSN (online)	2731-0590
DOI	10.1038/s44161-023-00272-4
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Article ; Online: Integrins are required for synchronous ommatidial rotation in the Drosophila eye linking planar cell polarity signalling to the extracellular matrix

Maria Thuveson / Konstantin Gaengel / Giovanna M. Collu / Mei-ling Chin / Jaskirat Singh / Marek Mlodzik

Open Biology, Vol 9, Iss

2019 Volume 8

Abstract	Integrins mediate the anchorage between cells and their environment, the extracellular matrix (ECM), and form transmembrane links between the ECM and the cytoskeleton, a conserved feature throughout development and morphogenesis of epithelial organs. Here, we demonstrate that integrins and components of the ECM are required during the planar cell polarity (PCP) signalling-regulated cell movement of ommatidial rotation in the Drosophila eye. The loss-of-function mutations of integrins or ECM components cause defects in rotation, with mutant clusters rotating asynchronously compared to wild-type clusters. Initially, mutant clusters tend to rotate faster, and at later stages they fail to be synchronous with their neighbours, leading to aberrant rotation angles and resulting in a disorganized ommatidial arrangement in adult eyes. We further demonstrate that integrin localization changes dynamically during the rotation process. Our data suggest that core Frizzled/PCP factors, acting through RhoA and Rho kinase, regulate the function/activity of integrins and that integrins thus contribute to the complex interaction network of PCP signalling, cell adhesion and cytoskeletal elements required for a precise and synchronous 90° rotation movement.
Keywords	planar cell polarity ; drosophila eye ; ommatidial rotation ; integrins ; extracellular matrix ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
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Article ; Online: Visualization of vascular mural cells in developing brain using genetically labeled transgenic reporter mice.

Jung, Bongnam / Arnold, Thomas D / Raschperger, Elisabeth / Gaengel, Konstantin / Betsholtz, Christer

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

2017 Volume 38, Issue 3, Page(s) 456–468

Abstract: The establishment of a fully functional blood vascular system requires elaborate angiogenic and vascular maturation events in order to fulfill organ-specific anatomical and physiological needs. Although vascular mural cells, i.e. pericytes and vascular ... ...

Abstract	The establishment of a fully functional blood vascular system requires elaborate angiogenic and vascular maturation events in order to fulfill organ-specific anatomical and physiological needs. Although vascular mural cells, i.e. pericytes and vascular smooth muscle cells, are known to play fundamental roles during these processes, their characteristics during vascular development remain incompletely understood. In this report, we utilized transgenic reporter mice in which mural cells are genetically labeled to examine developing vascular mural cells in the central nervous system (CNS). We found platelet-derived growth factor receptor β gene ( Pdgfrb)-driven EGFP reporter expression as a suitable marker for vascular mural cells at the earliest stages of mouse brain vascularization. Furthermore, the combination of Pdgfrb and NG2 gene (Cspg4) driven reporter expression increased the specificity of brain vascular mural cell labeling at later stages. The expression of other known pericyte markers revealed time-, region- and marker-specific patterns, suggesting heterogeneity in mural cell maturation. We conclude that transgenic reporter mice provide an important tool to explore the development of CNS pericytes in health and disease.
MeSH term(s)	Animals ; Antigens/genetics ; Blood Vessels/growth & development ; Blood Vessels/ultrastructure ; Brain/cytology ; Brain/growth & development ; Brain/ultrastructure ; Cerebral Cortex/growth & development ; Cerebral Cortex/ultrastructure ; Embryonic Development ; Female ; Genes, Reporter/genetics ; Mice ; Mice, Transgenic ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle/ultrastructure ; Pericytes/ultrastructure ; Proteoglycans/genetics ; Receptor, Platelet-Derived Growth Factor beta/genetics
Chemical Substances	Antigens ; Proteoglycans ; chondroitin sulfate proteoglycan 4 ; Receptor, Platelet-Derived Growth Factor beta (EC 2.7.10.1)
Language	English
Publishing date	2017-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604628-9
ISSN	1559-7016 ; 0271-678X
ISSN (online)	1559-7016
ISSN	0271-678X
DOI	10.1177/0271678X17697720
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