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1.
Biomed Pharmacother ; 154: 113630, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36058147

RESUMO

Gastric cancer (GC) is one of the most common gastrointestinal malignancies in the world. Growing evidence emphasizes the critical role of long non-coding RNA (lncRNA) in GC tumorigenesis. The aim of the research was to elucidate the effect and mechanism of Babao Dan (BBD) on lymphangiogenesis of GC in vitro and in vivo via lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis. The present study investigated BBD significantly decreased the expression of lncRNA-ANRIL and VEGF-C in GC cells (AGS, BGC823, and MGC80-3) by using real-time quantitative polymerasechain reaction (RT-qPCR) and the secretion and expression of VEGF-C by (enzyme linked immunosorbent assay) ELISA and western blot (WB). BBD significantly inhibited the tumor xenograft of GC growth and the expression of lncRNA-ANRIL, VEGF-C, VEGFR-3 and LYVE-1 in vivo. BBD reduced serum VEGF-C level. In vitro, BBD inhibited the tube formation and decreased the cell viability, proliferation and migration of HLECs by using tube formation, MTT, Hoechst and Transwell assays. In addition, WB assay found that BBD decreased the expression levels of VEGF-C, VEGFR-3, matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9), and RT-qPCR assay found that the mRNA expression levels of lncRNA-ANRIL, VEGF-C, VEGFR-3, MMP-2, MMP-9, CDK4, Cyclin D1, and Bcl-2 were down-regulated, and the expression of p21 and Bax were increased. Taken together, these results demonstrated that BBD inhibited lymphangiogenesis of GC in vitro and in vivo via the lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis.


Assuntos
RNA Longo não Codificante , Neoplasias Gástricas , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas , Humanos , Linfangiogênese/genética , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , RNA Longo não Codificante/genética , RNA Longo não Codificante/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Commun Biol ; 5(1): 950, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088423

RESUMO

Lymphangiogenesis is a key player in several diseases such as tumor metastasis, obesity, and graft rejection. Endogenous regulation of lymphangiogenesis is only partly understood. Here we use the normally avascular cornea as a model to identify endogenous regulators of lymphangiogenesis. Quantitative trait locus analysis of a large low-lymphangiogenic BALB/cN x high-lymphangiogenic C57BL/6 N intercross and prioritization by whole-transcriptome sequencing identify a novel gene responsible for differences in lymphatic vessel architecture on chromosome 17, the cystathionine ß-synthase (Cbs). Inhibition of CBS in lymphatic endothelial cells results in reduce proliferation, migration, altered tube-formation, and decrease expression of vascular endothelial growth factor (VEGF) receptor 2 (VEGF-R2) and VEGF-R3, but not their ligands VEGF-C and VEGF-D. Also in vivo inflammation-induced lymphangiogenesis is significantly reduce in C57BL/6 N mice after pharmacological inhibition of CBS. The results confirm CBS as a novel endogenous regulator of lymphangiogenesis acting via VEGF receptor 2 and 3-regulation and open new treatment avenues in diseases associated with pathologic lymphangiogenesis.


Assuntos
Cistationina beta-Sintase , Linfangiogênese , Animais , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Células Endoteliais/metabolismo , Linfangiogênese/genética , Camundongos , Camundongos Endogâmicos C57BL , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
PLoS One ; 17(9): e0273892, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36067135

RESUMO

Meningeal lymphatic vessels transport both the cerebrospinal fluid and interstitial fluid to the deep cervical lymph nodes. Traumatic brain injury (TBI) is accompanied by meningeal injury. We hypothesized that the TBI-induced meningeal injury would damage lymphatic vessels and affect brain function. We observed altered gene expression in meningeal lymphatic endothelial cells (LECs) in a mouse model of TBI. Through flow cytometry-based cell sorting, meningeal LECs were obtained from a mouse model of controlled cortical impact 3 days after TBI. Microarray analysis, real-time polymerase chain reaction assays, and enzyme-linked immunosorbent assays were performed to determine mRNA and protein expression levels in meningeal LECs. The number of meningeal LECs was significantly lower in the injury group than in the sham group 3 days after TBI. Additionally, the mRNA expression of lymphatic vessel endothelial hyaluronan receptor 1 (a specific marker of lymphatic vessels) in meningeal LECs was significantly lower in the injury group than in the sham group. The mRNA and protein expression of FMS-like tyrosine kinase 4 and neuropilin 2 (markers of lymphangiogenesis) in meningeal LECs was significantly higher in the injury group than in the sham group. Our findings indicate that TBI is associated with the impairment of meningeal LECs and meningeal lymphangiogenesis, which implicates lymphatic vessel injury in the pathogenesis of this condition.


Assuntos
Lesões Encefálicas Traumáticas , Vasos Linfáticos , Animais , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Células Endoteliais/metabolismo , Expressão Gênica , Linfangiogênese , Vasos Linfáticos/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
Int J Mol Sci ; 23(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35955568

RESUMO

There is evidence for increased angiogenesis in the (ectopic) endometrium of adenomyosis patients under the influence of vascular endothelial growth factor (VEGF). VEGF stimulates both angiogenesis and lymph-angiogenesis. However, information on lymph vessels in the (ectopic) endometrium of adenomyosis patients is lacking. In this retrospective matched case-control study, multiplex immunohistochemistry was performed on thirty-eight paraffin embedded specimens from premenopausal women who had undergone a hysterectomy at the Amsterdam UMC between 2001 and 2018 to investigate the evidence for (lymph) angiogenesis in the (ectopic) endometrium or myometrium of patients with adenomyosis versus controls with unrelated pathologies. Baseline characteristics of both groups were comparable. In the proliferative phase, the blood and lymph vessel densities were, respectively, higher in the ectopic and eutopic endometrium of patients with adenomyosis than in the endometrium of controls. The relative number of blood vessels without α-smooth muscle actinin (α SMA) was higher in the eutopic and ectopic endometrium of adenomyosis patients versus controls. The level of VEGF staining intensity was highest in the myometrium but did not differ between patients with adenomyosis or controls. The results indicate increased angiogenesis and lymphangiogenesis in the (ectopic) endometrium affected by adenomyosis. The clinical relevance of our findings should be confirmed in prospective clinical studies.


Assuntos
Adenomiose , Endometriose , Adenomiose/metabolismo , Adenomiose/patologia , Estudos de Casos e Controles , Endometriose/patologia , Endométrio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfangiogênese , Neovascularização Patológica/metabolismo , Estudos Prospectivos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
6.
Int Immunopharmacol ; 110: 109066, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35978512

RESUMO

BACKGROUND: Exosomes released from human umbilical cord mesenchymal stem cell (hucMSC-Ex) have been revealed to hold great potential for the development of new treatment approaches for various diseases, including inflammatory bowel disease (IBD). Lymphatic vessels are vital for IBD development and progression to colorectal cancer (CRC), as an occluded conduit for lymphatic fluid to return to the blood. OBJECTIVE: The mechanism involved remains largely unexplored. Here, we investigate the therapeutic effect of hucMSC-Ex in a mouse model of IBD during the modulation of lymphangiogenesis. METHODS: We established a dextran sulfate sodium (DSS)-induced IBD model in BALB/c mice and observed the influence of hucMSC-Ex on tissue repair, intestinal lymphatic function, changes in lymphangiogenesis, and infiltration of macrophages. We also evaluated the functional changes of human lymphatic endothelial cells (hLECs) in vitro to determine the mechanism by which hucMSC-Ex regulate lymphangiogenesis. Finally, we identified key molecules in hucMSC-Ex by sequencing, database comparison, and cell validation. RESULTS: Results showed that hucMSC-Ex alleviates IBD in mice by improving intestinal lymphatic drainage, inhibiting lymphangiogenesis, and infiltration of macrophages. Mechanistically, the miRNA sequencing results showed that miR-302d-3p was highly expressed in hucMSC-Ex and played an important role in inhibiting lymphangiogenesis by targeting Fms-related receptor tyrosine kinase 4 (FLT4). At the same time, the phosphorylation of AKT was inhibited and vascular endothelial growth factor receptor 3 (VEGFR3) was reduced. CONCLUSION: Collectively, our study suggests that hucMSC-Ex can regulate lymphangiogenesis via the miR-302d-3p/VEGFR3/AKT axis to ameliorate IBD. Our findings identify VEGFR3 as a potential therapeutic target in IBD, where tightly regulated lymphangiogenesis is crucial in its pathogenesis and progression.


Assuntos
Exossomos , Doenças Inflamatórias Intestinais , Células-Tronco Mesenquimais , MicroRNAs , Animais , Células Endoteliais , Exossomos/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Linfangiogênese , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cordão Umbilical , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/farmacologia
7.
Int J Mol Sci ; 23(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897834

RESUMO

Complex Lymphatic Anomalies (CLA) are lymphatic malformations with idiopathic bone and soft tissue involvement. The extent of the abnormal lymphatic presentation and boney invasion varies between subtypes of CLA. The etiology of these diseases has proven to be extremely elusive due to their rarity and irregular progression. In this review, we compiled literature on each of the four primary CLA subtypes and discuss their clinical presentation, lymphatic invasion, osseous profile, and regulatory pathways associated with abnormal bone loss caused by the lymphatic invasion. We highlight key proliferation and differentiation pathways shared between lymphatics and bone and how these systems may interact with each other to stimulate lymphangiogenesis and cause bone loss.


Assuntos
Doenças Ósseas , Anormalidades Linfáticas , Vasos Linfáticos , Doenças Ósseas/metabolismo , Osso e Ossos , Humanos , Linfangiogênese , Vasos Linfáticos/metabolismo
8.
Int J Mol Sci ; 23(13)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35805972

RESUMO

As an integral part of the vascular system, the lymphatic vasculature is essential for tissue fluid homeostasis, nutritional lipid assimilation and immune regulation. The composition of the lymphatic vasculature includes fluid-absorbing initial lymphatic vessels (LVs), transporting collecting vessels and anti-regurgitation valves. Although, in recent decades, research has drastically enlightened our view of LVs, investigations of initial LVs, also known as lymphatic capillaries, have been stagnant due to technical limitations. In the kidney, the lymphatic vasculature mainly presents in the cortex, keeping the local balance of fluid, solutes and immune cells. The contribution of renal LVs to various forms of pathology, especially chronic kidney diseases, has been addressed in previous studies, however with diverging and inconclusive results. In this review, we discuss the most recent advances in the proliferation and permeability of lymphatic capillaries as well as their influencing factors. Novel technologies to visualize and measure LVs function are described. Then, we highlight the role of the lymphatic network in renal fibrosis and the crosstalk between kidney and other organs, such as gut and heart.


Assuntos
Vasos Linfáticos , Insuficiência Renal Crônica , Fibrose , Humanos , Linfangiogênese/fisiologia , Sistema Linfático/patologia , Vasos Linfáticos/patologia , Insuficiência Renal Crônica/patologia
9.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806196

RESUMO

Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth. Consistently, MCF-7-CM induced ERK1/2 and Akt phosphorylation in VECs and inhibited them in LECs. Gene expression analysis revealed that the LECs were overall (≈10-fold) more sensitive to MCF-7-CM exposure than VECs. Growth/angiogenesis and cell cycle pathways were upregulated in VECs but downregulated in LECs. An angiogenesis proteome array confirmed the upregulation of 23 pro-angiogenesis proteins in VECs. In LECs, the expression of genes related to ATP synthesis and the ATP content were reduced by MCF-7-CM, whereas MTHFD2 gene, involved in folate metabolism and immune evasion, was upregulated. The contrasting effect of MCF-7-CM on the growth of VECs and LECs was reversed by inhibiting the TGF-ß signaling pathway. The effect of MCF-7-CM on VEC growth was also reversed by inhibiting the VEGF signaling pathway. In conclusion, BC secretome may facilitate cancer cell survival and tumor growth by simultaneously promoting vascular angiogenesis and inhibiting lymphatic growth. The differential effects of BC secretome on LECs and VECs may be of pathophysiological relevance in BC.


Assuntos
Neoplasias da Mama , Células Endoteliais , Trifosfato de Adenosina/metabolismo , Neoplasias da Mama/metabolismo , Células Endoteliais/metabolismo , Feminino , Humanos , Linfangiogênese/genética , Células MCF-7 , Neovascularização Patológica/metabolismo , Secretoma , Transcriptoma
10.
Cells ; 11(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35883582

RESUMO

(1) Background: Renal immune cells and lymphatic vessel (LV) density have been reported previously to be increased in multiple mouse models of hypertension (HTN). However, whether interstitial levels of HTN stimuli such as angiotensin II, salt, or asymmetric dimethylarginine have a direct or indirect effect on lymphangiogenesis is unknown. We hypothesized that these 3 HTN stimuli directly increase lymphatic endothelial cell (LEC) proliferation, LEC 3-D matrix invasion and vessel formation, and sprouting of mouse mesometrial LVs. (2) Methods: Human LECs (hLECs) and mouse LECs (mLECs) were treated with HTN stimuli while explanted mouse mesometrial LVs were treated with either the same HTN stimuli or with HTN stimuli-conditioned media. Conditioned media was prepared by treating murine splenocytes with HTN stimuli. (3) Results: HTN stimuli had no direct effect on hLEC or mLEC proliferation. Treatment of hLECs with HTN stimuli increased the number of lumen-forming structures and invasion distance (both p < 0.05) in the 3-D matrix but decreased the average lumen diameter and the number of cells per invading structure (both p < 0.05). Conditioned media from HTN-stimuli-treated splenocytes significantly attenuated the decrease in sprout number (aside from salt) and sprout length of mouse mesometrial LVs that is found in the HTN stimuli alone. (4) Conclusions: These data indicate that HTN stimuli indirectly prevent a decrease in lymphangiogenesis through secreted factors from HTN-stimuli-treated immune cells.


Assuntos
Hipertensão , Vasos Linfáticos , Animais , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais , Humanos , Linfangiogênese , Camundongos
11.
Breast Cancer Res Treat ; 195(1): 17-31, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35793004

RESUMO

PURPOSE: Platelet-derived growth factor B (PDGFB) is known to play essential roles in angiogenesis and lymphangiogenesis during development, and tumor growth and vessel stabilization in experimental models. However, whether these findings could be translated to breast cancer patients remains unclear. We hypothesized that PDGFB gene expression is associated with angiogenesis, cell proliferation, and clinical outcomes in breast cancer patients. METHODS: A total of 7635 primary breast cancer patients with full transcriptome and clinical data available from 13 independent cohorts were analyzed using in silico approach. The median value was used to divide each cohort into high and low PDGFB expression groups. RESULTS: High PDGFB gene expression was associated with increased expression of angiogenesis-related genes, higher amount of vascular cell infiltrations, and with enrichment of angiogenesis gene set, lymphangiogenesis-related gene expressions, lymphangiogenesis-related cell infiltrations, and enrichmentof lymphangiogenesis gene set in GSE96058 and validated by TCGA cohorts; however, not with lymphatic metastasis. PDGFB expression was neither associated with cell proliferation as assessed by Ki67 expression nor with Nottingham histological grade, or response to neoadjuvant chemotherapy. We found that PDGFB was most extensively expressed by endothelial and perivascular-like cells in the tumor microenvironment, and minimally by cancer cells consistently in two single-cell sequence cohorts. High PDGFB expression enriched TGFß, epithelial-mesenchymal transition, hypoxia, and cancer stem cell-associated pathways. However, no association with distant metastasis was observed. Disease-specific and disease-free survival were worse in the high PDGFB expression group consistently in TCGA and METABRIC cohorts. CONCLUSION: PDGFB is predominantly expressed in endothelial cells and is associated with angiogenesis and lymphangiogenesis, but not with cellular proliferation or metastasis in breast cancer.


Assuntos
Neoplasias da Mama , Linfangiogênese , Neoplasias da Mama/patologia , Células Endoteliais/metabolismo , Feminino , Genes sis , Humanos , Linfangiogênese/genética , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Microambiente Tumoral
12.
Artigo em Inglês | MEDLINE | ID: mdl-35879102

RESUMO

Blood vessels have a regulated permeability to fluid and solutes, which allows for the delivery of nutrients and signaling molecules to all cells in the body, a process essential to life. The lymphatic vasculature is the second network of vessels in the body, making up part of the immune system, yet is not typically thought of as having a permeability to fluid and solute. However, the major function of the lymphatic vasculature is to regulate tissue fluid balance to prevent edema, so lymphatic vessels must be permeable to absorb and transport fluid efficiently. Only recently were lymphatic vessels discovered to be permeable, which has had many functional implications. In this review, we will provide an overview of what is known about lymphatic vascular permeability, discuss the biophysical and signaling mechanisms regulating lymphatic permeability, and examine the disease relevance of this new property of lymphatic vessels.


Assuntos
Permeabilidade Capilar , Vasos Linfáticos , Humanos , Linfangiogênese/fisiologia , Vasos Linfáticos/fisiologia , Permeabilidade
13.
Cell Transplant ; 31: 9636897221107536, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35861534

RESUMO

Extracellular vesicles from adipose-derived mesenchymal stem cells (ADSCs) play an important role in lymphangiogenesis; however, the underlying mechanisms are not fully understood. In this study, we aimed to investigate the function of extracellular vesicles secreted by hypoxia-conditioned ADSCs in lymphangiogenesis and explore the potential molecular mechanisms. Extracellular vesicles were extracted from ADSCs cultured under hypoxia or normoxia conditions. The uptake of extracellular vesicles by lymphatic endothelial cells (LECs) was detected by immunofluorescence staining. The effects of extracellular vesicles on the viability, migration, and tube formation of LECs were determined by CCK-8 assay, migration assay, and tube formation assay, respectively. Molecules and pathway involved in lymphangiogenesis mediated by ADSC-derived extracellular vesicles were analyzed by luciferase reporter assay, qRT-polymerase chain reaction (PCR), and Western blot. Hypoxia ADSC-derived extracellular vesicles (H-ADSC/evs) significantly enhanced the proliferation, migration, and tube formation of LECs. Hypoxia decreased the expression of miR-129 in ADSC-derived extracellular vesicles. Overexpression of miR-129 counteracted the promoting effect of H-ADSC/evs on lymphangiogenesis. In addition, decreased exosomal miR-129 expression resulted in upregulation of HMGB1 in LECs, which led to AKT activation and lymphangiogenesis enhancement. Our data reveal that extracellular vesicles derived from hypoxia-conditioned ADSCs induce lymphangiogenesis, and this effect is mediated by miR-129/HMGB1/AKT signaling. Our findings imply that hypoxia ADSC-isolated extracellular vesicles may represent as a valuable target for the treatment of diseases associated with lymphatic remodeling.


Assuntos
Vesículas Extracelulares , Proteína HMGB1 , Células-Tronco Mesenquimais , MicroRNAs , Tecido Adiposo , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Humanos , Hipóxia/metabolismo , Linfangiogênese , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
14.
J Clin Invest ; 132(14)2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35838046

RESUMO

Kirsten rat sarcoma virus (KRAS) gene mutations are present in more than 90% of pancreatic ductal adenocarcinomas (PDACs). KRASG12D is the most frequent alteration, promoting preneoplastic lesions and associating with a more aggressive phenotype. These tumors possess increased intratumoral lymphatic networks and frequent lymph node (LN) metastases. In this issue of the JCI, Luo, Li, et al. explored the relationship between the presence of the KRASG12D mutation and lymphangiogenesis in PDAC. The authors used in vitro and in vivo models and an elegant mechanistic approach to describe an alternative pathway for lymphangiogenesis promotion. KRASG12D induced SUMOylation of heterogenous nuclear ribonucleoprotein A1 (hnRNPA1) via SAE1 and SUMO2 activation. SUMOylated hnRNPA1 was loaded into extracellular vesicles (EVs) and internalized by human endothelial lymphatic cells (HLEC). Further, SUMOylated hnRNPA1 promoted lymphangiogenesis and LN metastasis by stabilizing prospero homeodomain protein 1 (PROX1) mRNA. These data provide mechanistic insight into cancer lymphangiogenesis with the potential for developing biomarkers and RAS pathway therapeutics.


Assuntos
Vesículas Extracelulares , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Vesículas Extracelulares/metabolismo , Humanos , Vírus do Sarcoma Murino de Kirsten/metabolismo , Linfangiogênese/genética , Metástase Linfática , Mutação , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
15.
Cells ; 11(11)2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35681445

RESUMO

The lymphatic system is pivotal for immunosurveillance and the maintenance of tissue homeostasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, has both physiological and pathological roles. Recent advances in the molecular mechanisms regulating lymphangiogenesis have opened a new area of research on reparative lymphangiogenesis for the treatment of various pathological disorders comprising neurological disorders, cardiac repair, autoimmune disease, obesity, atherosclerosis, etc. Reactive oxygen species (ROS) produced by the various cell types serve as signaling molecules in several cellular mechanisms and regulate various aspects of growth-factor-mediated responses, including lymphangiogenesis. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Low ROS levels are essential for lymphangiogenesis. On the contrary, oxidative stress due to enhanced ROS generation and/or reduced levels of antioxidants suppresses lymphangiogenesis via promoting lymphatic endothelial cell apoptosis and death. In this review article, we provide an overview of types and sources of ROS, discuss the role of ROS in governing lymphangiogenesis and lymphatic function, and summarize the role of lymphatics in various diseases.


Assuntos
Linfangiogênese , Vasos Linfáticos , Células Endoteliais/metabolismo , Sistema Linfático , Espécies Reativas de Oxigênio/metabolismo
16.
Cell Rep ; 39(12): 110982, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35732122

RESUMO

Lymphangiogenesis, formation of lymphatic vessels from pre-existing vessels, is a dynamic process that requires cell migration. Regardless of location, migrating lymphatic endothelial cell (LEC) progenitors probe their surroundings to form the lymphatic network. Lymphatic-development regulation requires the transcription factor MAFB in different species. Zebrafish Mafba, expressed in LEC progenitors, is essential for their migration in the trunk. However, the transcriptional mechanism that orchestrates LEC migration in different lymphatic endothelial beds remains elusive. Here, we uncover topographically different requirements of the two paralogs, Mafba and Mafbb, for LEC migration. Both mafba and mafbb are necessary for facial lymphatic development, but mafbb is dispensable for trunk lymphatic development. On the molecular level, we demonstrate a regulatory network where Vegfc-Vegfd-SoxF-Mafba-Mafbb is essential in facial lymphangiogenesis. We identify that mafba and mafbb tune the directionality of LEC migration and vessel morphogenesis that is ultimately necessary for lymphatic function.


Assuntos
Vasos Linfáticos , Peixe-Zebra , Animais , Movimento Celular , Células Endoteliais , Linfangiogênese , Morfogênese , Transdução de Sinais
17.
Front Cell Infect Microbiol ; 12: 824575, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35646744

RESUMO

Lymphangiogenesis and angiogenesis might have significant involvement in the pathogenesis of otitis media with effusion. This study investigated the effect of diesel exhaust particles (DEP) on inflammation and lymphangiogenesis in a mouse model of acute otitis media (AOM). BALB/c mice were injected with LPS and exposed to 100 µg/m3 DEP. The mice were divided into four groups: control (no stimulation), AOM, AOM + DEP, and DEP + AOM. The effects of DEP inhalation pre- and post-DEP induction were estimated based on measurements of the auditory brainstem response, mRNA levels of lymphangiogenesis-related genes and cytokines, and histology of the middle ear. Cell viability of human middle ear epithelial cells decreased in a dose-response manner at 24 and 48 hours post-DEP exposure. DEP alone did not induce AOM. AOM-induced mice with pre- or post-DEP exposure showed thickened middle ear mucosa and increased expression of TNF-α and IL1-ß mRNA levels compared to the control group, but increased serum IL-1ß levels were not found in the AOM + Post DEP. The mRNA expression of TLR4, VEGFA, VEGFAC, and VEGFR3 was increased by pre-AOM DEP exposure. The expression of VEFGA protein was stronger in the AOM + Post DEP group than in any other group. The expression of CD31 and CD45 markers in the mouse middle ear tissue was higher in the Pre DEP + AOM group than in the AOM group. This result implies that pre-exposure to DEP more strongly increases inflammation and lymphangiogenesis in a mouse model of acute otitis media.


Assuntos
Otite Média , Emissões de Veículos , Animais , Modelos Animais de Doenças , Inflamação , Lipopolissacarídeos/toxicidade , Linfangiogênese , Camundongos , Camundongos Endogâmicos BALB C , Otite Média/induzido quimicamente , Otite Média/metabolismo , RNA Mensageiro/metabolismo , Emissões de Veículos/toxicidade
18.
Biomolecules ; 12(6)2022 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-35740945

RESUMO

Peripheral nerve injuries pose a major clinical concern world-wide, and functional recovery after segmental peripheral nerve injury is often unsatisfactory, even in cases of autografting. Although it is well established that angiogenesis plays a pivotal role during nerve regeneration, the influence of lymphangiogenesis is strongly under-investigated. In this study, we analyzed the presence of lymphatic vasculature in healthy and regenerated murine peripheral nerves, revealing that nerve autografts contained increased numbers of lymphatic vessels after segmental damage. This led us to elucidate the interaction between lymphatic endothelial cells (LECs) and Schwann cells (SCs) in vitro. We show that SC and LEC secretomes did not influence the respective other cell types' migration and proliferation in 2D scratch assay experiments. Furthermore, we successfully created lymphatic microvascular structures in SC-embedded 3D fibrin hydrogels, in the presence of supporting cells; whereas SCs seemed to exert anti-lymphangiogenic effects when cultured with LECs alone. Here, we describe, for the first time, increased lymphangiogenesis after peripheral nerve injury and repair. Furthermore, our findings indicate a potential lymph-repellent property of SCs, thereby providing a possible explanation for the lack of lymphatic vessels in the healthy endoneurium. Our results highlight the importance of elucidating the molecular mechanisms of SC-LEC interaction.


Assuntos
Linfangiogênese , Traumatismos dos Nervos Periféricos , Animais , Apoptose , Autoenxertos , Células Endoteliais/fisiologia , Camundongos , Células de Schwann , Transplante Autólogo
19.
Adv Healthc Mater ; 11(16): e2200464, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35678079

RESUMO

Preparation of human mesenchymal stem cell (hMSC) suspension for lymphedema treatment relies on conventional enzymatic digestion methods, which severely disrupts cell-cell and cell-extracellular matrix (ECM) connections, and drastically impairs cell retention and engraftment after transplantation. The objective of the present study is to evaluate the ability of hMSC-secreted ECM to augment lymphangiogenesis by using an in vitro coculturing model of hMSC sheets with lymphatic endothelial cells (LECs) and an in vivo mouse tail lymphedema model. Results demonstrate that the hMSC-secreted ECM augments the formation of lymphatic capillary-like structure by a factor of 1.2-3.6 relative to the hMSC control group, by serving as a prolymphangiogenic growth factor reservoir and facilitating cell regenerative activities. hMSC-derived ECM enhances MMP-2 mediated matrix remodeling, increases the synthesis of collagen IV and laminin, and promotes lymphatic microvessel-like structure formation. The injection of rat MSC sheet fragments into a mouse tail lymphedema model confirms the benefits of the hMSC-derived ECM by stimulating lymphangiogenesis and wound closure.


Assuntos
Linfangiogênese , Células-Tronco Mesenquimais , Animais , Células Endoteliais , Humanos , Vasos Linfáticos , Linfedema/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Ratos
20.
Physiol Rev ; 102(4): 1837-1879, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35771983

RESUMO

The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an essential transport system for fluids, biomolecules, and cells between peripheral tissues and the central circulation. Consequently, it is required for normal body physiology but is also involved in the pathogenesis of various diseases, most notably cancer. The important role of tumor-associated lymphatic vessels and lymphangiogenesis in the formation of lymph node metastasis has been elucidated during the last two decades, whereas the underlying mechanisms and the relation between lymphatic and peripheral organ dissemination of cancer cells are incompletely understood. Lymphatic vessels are also important for tumor-host communication, relaying molecular information from a primary or metastatic tumor to regional lymph nodes and the circulatory system. Beyond antigen transport, lymphatic endothelial cells, particularly those residing in lymph node sinuses, have recently been recognized as direct regulators of tumor immunity and immunotherapy responsiveness, presenting tumor antigens and expressing several immune-modulatory signals including PD-L1. In this review, we summarize recent discoveries in this rapidly evolving field and highlight strategies and challenges of therapeutic targeting of lymphatic vessels or specific lymphatic functions in cancer patients.


Assuntos
Células Endoteliais , Vasos Linfáticos , Humanos , Imunoterapia , Linfangiogênese , Metástase Linfática/patologia
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