Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade

Objective— AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. Approach and Results— Human primary lymph node–derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node–derived lymphatic endothelial cells and activating the Akt/extracellular signal–regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node–derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. Conclusions— Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.

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Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2015.2 ◽

2015 ◽

Vol 17 ◽

Cited By ~ 41

Author(s):

Esak Lee ◽

Niranjan B. Pandey ◽

Aleksander S. Popel

Keyword(s):

Endothelial Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Tumour Growth ◽

Tumour Progression ◽

Lymphatic Vessels ◽

Cell Types ◽

Malignant Cell ◽

Lymphatic Endothelial Cells ◽

Tumour Blood

Tumour and organ microenvironments are crucial for cancer progression and metastasis. Crosstalk between multiple non-malignant cell types in the microenvironments and cancer cells promotes tumour growth and metastasis. Blood and lymphatic endothelial cells (BEC and LEC) are two of the components in the microenvironments. Tumour blood vessels (BV), comprising BEC, serve as conduits for blood supply into the tumour, and are important for tumour growth as well as haematogenous tumour dissemination. Lymphatic vessels (LV), comprising LEC, which are relatively leaky compared with BV, are essential for lymphogenous tumour dissemination. In addition to describing the conventional roles of the BV and LV, we also discuss newly emerging roles of these endothelial cells: their crosstalk with cancer cells via molecules secreted by the BEC and LEC (also called angiocrine and lymphangiocrine factors). This review suggests that BEC and LEC in various microenvironments can be orchestrators of tumour progression and proposes new mechanism-based strategies to discover new therapies to supplement conventional anti-angiogenic and anti-lymphangiogenic therapies.

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Organ-specific lymphatic vasculature: From development to pathophysiology

Journal of Experimental Medicine ◽

10.1084/jem.20171868 ◽

2017 ◽

Vol 215 (1) ◽

pp. 35-49 ◽

Cited By ~ 88

Author(s):

Tatiana V. Petrova ◽

Gou Young Koh

Keyword(s):

Endothelial Cells ◽

Dietary Fat ◽

Lymphatic Vessels ◽

Developmental Origins ◽

Lymphatic Endothelial Cells ◽

Tissue Microenvironment ◽

Organ Specific ◽

Intestinal Lymphatics ◽

Lymphatic Vasculature ◽

Fat Uptake

Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood-lymphatic identity of Schlemm’s canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells.

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Vascular Growth Factors and Lymphangiogenesis

Physiological Reviews ◽

10.1152/physrev.00005.2002 ◽

2002 ◽

Vol 82 (3) ◽

pp. 673-700 ◽

Cited By ~ 260

Author(s):

Lotta Jussila ◽

Kari Alitalo

Keyword(s):

Endothelial Cells ◽

Growth Factors ◽

Lymphatic System ◽

Lymphatic Vessels ◽

The Body ◽

Vascular Tumors ◽

Vascular Endothelial ◽

Lymphatic Endothelial Cells ◽

Independent Manner ◽

Tumor Spread

Blood and lymphatic vessels develop in a parallel, but independent manner, and together form the circulatory system allowing the passage of fluid and delivering molecules within the body. Although the lymphatic vessels were discovered already 300 years ago, at the same time as the blood circulation was described, the lymphatic system has remained relatively neglected until recently. This is in part due to the difficulties in recognizing these vessels in tissues because of a lack of specific markers. Over the past few years, several molecules expressed specifically in the lymphatic endothelial cells have been characterized, and knowledge about the lymphatic system has started to accumulate again. The vascular endothelial growth factor (VEGF) family of growth factors and receptors is involved in the development and growth of the vascular endothelial system. Two of its family members, VEGF-C and VEGF-D, regulate the lymphatic endothelial cells via their receptor VEGFR-3. With the aid of these molecules, lymphatic endothelial cells can be isolated and cultured, allowing detailed studies of the molecular properties of these cells. Also the role of the lymphatic endothelium in immune responses and certain pathological conditions can be studied in more detail, as the blood and lymphatic vessels seem to be involved in many diseases in a coordinated manner. Discoveries made so far will be helpful in the diagnosis of certain vascular tumors, in the design of specific treatments for lymphedema, and in the prevention of metastatic tumor spread via the lymphatic system.

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Endothelin-1 cooperates with hypoxia to induce vascular-like structures through vascular endothelial growth factor-C, -D and -A in lymphatic endothelial cells

Life Sciences ◽

10.1016/j.lfs.2012.03.033 ◽

2012 ◽

Vol 91 (13-14) ◽

pp. 638-643 ◽

Cited By ~ 13

Author(s):

Emirena Garrafa ◽

Valentina Caprara ◽

Valeriana Di Castro ◽

Laura Rosanò ◽

Anna Bagnato ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Vascular Endothelial ◽

Lymphatic Endothelial Cells ◽

Endothelin 1 ◽

Factor C ◽

Endothelial Growth Factor

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Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes

10.1101/2020.01.09.900241 ◽

2020 ◽

Cited By ~ 1

Author(s):

Noriki Fujimoto ◽

Yuliang He ◽

Marco D’Addio ◽

Carlotta Tacconi ◽

Michael Detmar ◽

...

Keyword(s):

Endothelial Cells ◽

Immune Responses ◽

Lymph Nodes ◽

Single Cell ◽

Cancer Metastasis ◽

Lymphatic Vessels ◽

Peripheral Tolerance ◽

Lymphatic Endothelial Cells ◽

Subcapsular Sinus ◽

Lymphocyte Egress

ABSTRACTLymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs, and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus have an unanticipated function in scavenging of modified LDL and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new insights into the diversity of LECs in murine lymph nodes and a rich resource for future studies into the regulation of immune responses by lymph node LECs.

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Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells

10.1101/2021.06.30.450504 ◽

2021 ◽

Author(s):

Di Peng ◽

Koji Ando ◽

Marleen Gloger ◽

Renae Skoczylas ◽

Naoki Mochizuki ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Lymphatic Vessels ◽

Vascular Network ◽

Lymphatic Endothelial Cells ◽

Future Design ◽

Mural Cells ◽

Cell Ablation ◽

Growth Factor Signalling ◽

Factor C

The migration of lymphatic endothelial cells (LECs) is key for the development of the complex and vast lymphatic vascular network that pervades most of the tissues in an organism. In zebrafish, arterial intersegmental vessels together with chemokines have been shown to promote lymphatic cell migration from the horizontal myoseptum (HM). Here we found that LECs departure from HM coincides with the emergence of mural cells around the intersegmental arteries, raising the possibility that arterial mural cells promote LEC migration. Our live imaging and cell ablation experiments revealed that LECs migrate slower and fail to establish the lymphatic vascular network in the absence of arterial mural cells. We determined that mural cells are a source for the C-X-C motif chemokine 12 (Cxcl12a and Cxcl12b) and vascular endothelial growth factor C (Vegfc). We showed that ERK, a downstream component of Vegfc-Vegfr3 singling cascade, is activated in migrating LECs and that both chemokine and growth factor signalling is required for the robust migration. Furthermore, Vegfc-Vegfr3 has a pro-survival role in LECs during the migration. Together, the identification of mural cells a source for signals that guide LEC migration and survival will be important in the future design for rebuilding lymphatic vessels in the disease contexts.

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Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges

Acta Neuropathologica ◽

10.1007/s00401-019-02091-z ◽

2019 ◽

Vol 139 (2) ◽

pp. 383-401 ◽

Cited By ~ 5

Author(s):

Shannon Shibata-Germanos ◽

James R. Goodman ◽

Alan Grieg ◽

Chintan A. Trivedi ◽

Bridget C. Benson ◽

...

Keyword(s):

Endothelial Cells ◽

Dura Mater ◽

Lymphatic Vessels ◽

Amyloid Β ◽

Lymphatic Endothelial Cells ◽

Cell Type ◽

Functional Conservation ◽

Spherical Inclusions ◽

Lymphatic Markers ◽

The Brain

Abstract The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain or leptomeninges. However, non-lumenized cells called Brain/Mural Lymphatic Endothelial Cells or Fluorescent Granule Perithelial cells (muLECs/BLECs/FGPs) that share a developmental program and gene expression with peripheral lymphatic vessels have been described in the meninges of zebrafish. Here we identify a structurally and functionally similar cell type in the mammalian leptomeninges that we name Leptomeningeal Lymphatic Endothelial Cells (LLEC). As in zebrafish, LLECs express multiple lymphatic markers, containing very large, spherical inclusions, and develop independently from the meningeal macrophage lineage. Mouse LLECs also internalize macromolecules from the cerebrospinal fluid, including Amyloid-β, the toxic driver of Alzheimer’s disease progression. Finally, we identify morphologically similar cells co-expressing LLEC markers in human post-mortem leptomeninges. Given that LLECs share molecular, morphological, and functional characteristics with both lymphatics and macrophages, we propose they represent a novel, evolutionary conserved cell type with potential roles in homeostasis and immune organization of the meninges.

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Sphingosine 1-phosphate receptor 1 regulates the directional migration of lymphatic endothelial cells in response to fluid shear stress

Journal of The Royal Society Interface ◽

10.1098/rsif.2016.0823 ◽

2016 ◽

Vol 13 (125) ◽

pp. 20160823 ◽

Cited By ~ 6

Author(s):

Vinay N. Surya ◽

Eleftheria Michalaki ◽

Eva Y. Huang ◽

Gerald G. Fuller ◽

Alexander R. Dunn

Keyword(s):

Endothelial Cells ◽

Fluid Flow ◽

Molecular Mechanisms ◽

Fluid Shear Stress ◽

Lymphatic Vessels ◽

Upstream Migration ◽

Lymphatic Endothelial Cells ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled

The endothelial cells that line blood and lymphatic vessels undergo complex, collective migration and rearrangement processes during embryonic development, and are known to be exquisitely responsive to fluid flow. At present, the molecular mechanisms by which endothelial cells sense fluid flow remain incompletely understood. Here, we report that both the G-protein-coupled receptor sphingosine 1-phosphate receptor 1 (S1PR1) and its ligand sphingosine 1-phosphate (S1P) are required for collective upstream migration of human lymphatic microvascular endothelial cells in an in vitro setting. These findings are consistent with a model in which signalling via S1P and S1PR1 are integral components in the response of lymphatic endothelial cells to the stimulus provided by fluid flow.

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ALK1 signaling regulates early postnatal lymphatic vessel development

Blood ◽

10.1182/blood-2009-07-235655 ◽

2010 ◽

Vol 115 (8) ◽

pp. 1654-1661 ◽

Cited By ~ 71

Author(s):

Kyle Niessen ◽

Gu Zhang ◽

John Brady Ridgway ◽

Hao Chen ◽

Minhong Yan

Keyword(s):

Endothelial Cells ◽

Transforming Growth Factor ◽

Vascular Development ◽

Lymphatic Vessels ◽

Transforming Growth Factor Β ◽

Type I ◽

Lymphatic Endothelial Cells ◽

Multiple Organs ◽

Lymphatic Development

Abstract In vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

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