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| Open AccessSelf-organized and directed branching results in optimal coverage in developing dermal lymphatic networks
The lymphatic system is a transport network that controls immune response and tissue fluid circulation in the body. Here the authors combine experiment and theory to reveal that developing lymphatic capillary networks exploit complementary branching strategies to optimize tissue coverage.
- Mehmet Can Uçar
- , Edouard Hannezo
- & Kari Vaahtomeri
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Article
| Open AccessLoss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures
Loss of canonical Notch signaling in vascular endothelial cells induces spontaneous formation of proto-typical tertiary lymphoid structures in mouse kidney, liver and lungs, which form around central arteries that acquire a high endothelial cell signature
- Susanne Fleig
- , Tamar Kapanadze
- & Florian P. Limbourg
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Article
| Open AccessTargeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.
- Dali Zhang
- , Junlan Huang
- & Yangli Xie
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Article
| Open AccessNucleoside-modified VEGFC mRNA induces organ-specific lymphatic growth and reverses experimental lymphedema
Dysfunction of the lymphatic system leads to secondary lymphedema and results in degradation of quality of life. Here, the authors show that delivery of nucleoside-modified Vascular Endothelial Growth Factor C (VEGFC) mRNA, encapsulated in lipid nanoparticles, induces organ-specific lymphatic growth and reverses experimental lymphedema.
- Dániel Szőke
- , Gábor Kovács
- & Zoltán Jakus
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Article
| Open AccessBlood and lymphatic systems are segregated by the FLCN tumor suppressor
Blood and lymphatic vessels bear a strong resemblance but do not share a lumen, thus maintaining their distinct functions. Here, the authors describe that Folliculin, a tumor suppressor, prevents the fusion of these vessels during development by limiting the plasticity of venous and lymphatic endothelial cells.
- Ikue Tai-Nagara
- , Yukiko Hasumi
- & Yoshiaki Kubota
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Article
| Open AccessDistinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi
Intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. Here the authors show that VEGF-C expression in specialized IntSCs is regulated by YAP/TAZ, and VEGF-C is responsible for maintaining lacteal integrity, thus influencing dietary fat drainage into lacteals.
- Seon Pyo Hong
- , Myung Jin Yang
- & Gou Young Koh
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Article
| Open AccessBlockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.
- Ines Martinez-Corral
- , Yan Zhang
- & Taija Mäkinen
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| Open AccessSpecific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis
How and where VEGF-C is processed in lymphangiogenesis is unclear. Here, the authors show that development of the zebrafish lymphatic system is locally restricted by Vegfc maturation causing lymphatic sprouting in certain regions, which is regulated by the metalloproteases ADAMTS3 and ADAMTS14.
- Guangxia Wang
- , Lars Muhl
- & Andreas van Impel
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Article
| Open AccessNeuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells
Lymphangiogenesis occurs in the context of systemic inflammation and development but has not been reported for the lymphatics that surround the CNS. Here the authors show that in the context of experimental autoimmune encephatlitis, lymphangiogenesis occurs at the cribriform plate, but not the meninges, and contributes to immune cell and antigen drainage.
- Martin Hsu
- , Aditya Rayasam
- & Zsuzsanna Fabry
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Article
| Open AccessuPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis
VEGF-C drives lymphangiogenesis through binding to its receptors VEGFR-2 and VEGFR-3. Here, Durré et al. identify uPARAP/Endo180 as a critical regulator of VEGFR-2/VEGFR-3 heterodimerisation and downstream signaling in response to VEGF-C, and show that uPARAP deletion leads to the formation of hyperbranched vasculatures in pathological conditions.
- Tania Durré
- , Florent Morfoisse
- & Agnès Noel
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Article
| Open AccessHHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development
VEGFC, its receptor FLT4, and transcriptional effector PROX1 control formation of the lymphatic system but how is unclear. Here, the authors show that the transcription factor hematopoietically expressed homeobox (HHEX) regulates VEGFC, FLT4 and PROX1 in fish and mammals during angiogenic sprouting and lymphatic formation.
- Sébastien Gauvrit
- , Alethia Villasenor
- & Didier Y. R. Stainier
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Article
| Open AccessMatrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
Mechanical cues are known to influence endothelial cell behavior. Here Frye et al. show that lymphatic endothelial cell progenitors experience varying degrees of matrix stiffness during development, and that matrix stiffness regulates GATA2 expression to drive lymphatic vessel formation.
- Maike Frye
- , Andrea Taddei
- & Taija Mäkinen
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Article
| Open AccessHeterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms
VEGF-C is a key regulator of lymphatic development. Here, Zhang et al. show that while complete loss of its receptor VEGFR3 results in vessel hypoplasia, mosaic loss of VEGFR3 leads to hyperplasia through induction of cell proliferation in neighboringnon-targeted cells, uncovering cell- and non-cell-autonomous roles for VEGFR3 during lymphatic vessel growth.
- Yan Zhang
- , Maria H. Ulvmar
- & Taija Mäkinen
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Article
| Open AccessInteractions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis
The growth of lymph nodes in response to infection requires lymphangiogenesis. Dubey et al. show that the mesenteric lymph node lymphangiogenesis upon helminth infection depends on the signaling loop between the B and fibroblastic reticular cells (FRCs), whereby the FRCs respond to lymphotoxin secreted by B cells by releasing B cell activating factor.
- Lalit Kumar Dubey
- , Praneeth Karempudi
- & Nicola L. Harris
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Article
| Open AccessPathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3
Pathological lymphangiogenesis is associated with various eye diseases. Here the authors show that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis in the eye by regulating the crosstalk among VEGF-C, podoplanin and integrin pathways, and thus may represent a useful therapeutic target.
- Wei-Sheng Chen
- , Zhiyi Cao
- & Noorjahan Panjwani
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Article
| Open AccessMT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis
Blocking lymphangiogenesis holds great therapeutic potential, however, only few inhibitors are known. Here the authors show that membrane type 1-matrix metalloproteinase suppresses lymphangiogenesis by curbing both LYVE-1-mediated proliferation of lymphatic endothelial cells and production of lymphangiogenic factors by macrophages.
- Hoi Leong Xavier Wong
- , Guoxiang Jin
- & Zhongjun Zhou
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Article |
Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2
The mechanisms regulating lymphatic vessel development and function are still largely unknown. Here, the authors show that the protein kinase Cdk5 is required for lymphatic vessel development by regulating the activity of the transcription factor Foxc2 and its target genes.
- Johanna Liebl
- , Siwei Zhang
- & Stefan Zahler
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Article
| Open AccessEphB4 forward signalling regulates lymphatic valve development
The bidirectional Eph-ephrin signalling regulates a myriad of developmental programmes. Zhang et al. show that EphB4 forward signalling is crucial for lymphatic valve development, providing new insight into this important developmental process previously thought to be regulated by ephrinB2-dependent reverse signalling.
- Gu Zhang
- , John Brady
- & Minhong Yan
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Article
| Open AccessRhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription
The formation of blood and lymph vessels after injury requires precise temporal coordination. Here, the authors show that the small GTPase RhoB induces angiogenesis but inhibits lymphangiogenesis in response to dermal wounding by activating different sets of genes in blood vessels and lymphatic endothelial cells.
- Damien Gerald
- , Irit Adini
- & Laura E. Benjamin