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1.
J Int Med Res ; 52(3): 3000605241234558, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38518198

RESUMO

OBJECTIVE: To investigate the roles and underlying mechanisms of vascular endothelial growth factor receptor-3 (VEGFR-3) in gastric cancer (GC). METHODS: VEGFR-3 gene expression profiles in human gastric adenocarcinoma (GAC) tissues were analysed using The Cancer Genome Atlas database. Human GC cell lines and were used for in vitro studies. Mouse models of GC and distant metastasis were used for in vivo studies. Silencing of VEGFR-3 gene expression was achieved using small interfering RNA. RESULTS: VEGFR-3 gene expression was significantly elevated in GAC tissues and GC cells. Higher VEGFR-3 expression was positively correlated with more advanced stages and a greater number of metastatic lymph nodes. In vitro studies in GC cells showed that knockdown of VEGFR-3 gene expression significantly suppressed cell proliferation and migration, but promoted apoptosis. In vivo investigations revealed that silencing of VEGFR-3 gene expression exhibited significant inhibition on tumour growth and metastasis. Further mechanistic studies showed that VEGFR-3 exerted its pathological roles by affecting the key molecules in the apoptotic and epithelial-mesenchymal transition pathways. CONCLUSION: The molecular pathways associated with VEGFR-3-mediated pathological effects could be targets in the development of novel approaches for the diagnosis, prognosis and treatment of GC.


Assuntos
Neoplasias Gástricas , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Animais , Camundongos , Humanos , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Prognóstico , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/farmacologia
2.
Front Immunol ; 15: 1349500, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38464522

RESUMO

Lymphatic vessels have been increasingly appreciated in the context of immunology not only as passive conduits for immune and cancer cell transport but also as key in local tissue immunomodulation. Targeting lymphatic vessel growth and potential immune regulation often takes advantage of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling to manipulate lymphatic biology. A receptor tyrosine kinase, VEGFR-3, is highly expressed on lymphatic endothelial cells, and its signaling is key in lymphatic growth, development, and survival and, as a result, often considered to be "lymphatic-specific" in adults. A subset of immune cells, notably of the monocyte-derived lineage, have been identified to express VEGFR-3 in tissues from the lung to the gut and in conditions as varied as cancer and chronic kidney disease. These VEGFR-3+ macrophages are highly chemotactic toward the VEGFR-3 ligands VEGF-C and VEGF-D. VEGFR-3 signaling has also been implicated in dictating the plasticity of these cells from pro-inflammatory to anti-inflammatory phenotypes. Conversely, expression may potentially be transient during monocyte differentiation with unknown effects. Macrophages play critically important and varied roles in the onset and resolution of inflammation, tissue remodeling, and vasculogenesis: targeting lymphatic vessel growth and immunomodulation by manipulating VEGFR-3 signaling may thus impact macrophage biology and their impact on disease pathogenesis. This mini review highlights the studies and pathologies in which VEGFR-3+ macrophages have been specifically identified, as well as the activity and polarization changes that macrophage VEGFR-3 signaling may elicit, and affords some conclusions as to the importance of macrophage VEGFR-3 signaling in disease.


Assuntos
Linfangiogênese , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Linfangiogênese/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Macrófagos/metabolismo
3.
JCI Insight ; 9(1)2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-37971881

RESUMO

The lymphatic vasculature is the natural pathway for the resolution of inflammation, yet the role of pulmonary lymphatic drainage function in sepsis-induced acute respiratory distress syndrome (ARDS) remains poorly characterized. In this study, indocyanine green-near infrared lymphatic living imaging was performed to examine pulmonary lymphatic drainage function in septic mouse models. We found that the pulmonary lymphatic drainage was impaired owing to the damaged lymphatic structure in sepsis-induced ARDS. Moreover, prior lymphatic defects by blocking vascular endothelial growth factor receptor-3 (VEGFR-3) worsened sepsis-induced lymphatic dysfunction and inflammation. Posttreatment with vascular endothelial growth factor-C (Cys156Ser) (VEGF-C156S), a ligand of VEGFR-3, ameliorated lymphatic drainage by rejuvenating lymphatics to reduce the pulmonary edema and promote draining of pulmonary macrophages and neutrophils to pretracheal lymph nodes. Meanwhile, VEGF-C156S posttreatment reversed sepsis-inhibited CC chemokine ligand 21 (CCL21), which colocalizes with pulmonary lymphatic vessels. Furthermore, the advantages of VEGF-C156S on the drainage of inflammatory cells and edema fluid were abolished by blocking VEGFR-3 or CCL21. These results suggest that efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. Our findings offer a therapeutic approach to sepsis-induced ARDS by promoting lymphatic drainage function.


Assuntos
Vasos Linfáticos , Síndrome do Desconforto Respiratório , Sepse , Camundongos , Animais , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ligantes , Vasos Linfáticos/patologia , Inflamação/metabolismo , Síndrome do Desconforto Respiratório/patologia , Sepse/metabolismo
4.
Cell Adh Migr ; 17(1): 1-14, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37889090

RESUMO

Lymphangiogenesis plays pivotal roles in diverse physiological and pathological conditions. Steady direct-current electric fields (DC EFs) induce vascular endothelial behaviors related to angiogenesis have been observed. This study investigated the effects of DC EFs on the lymphangiogenic response of lymphatic endothelial cells (LECs). We demonstrated that EFs stimulation induced directional migration, reorientation, and elongation of human LECs in culture. These lymphangiogenic responses required VEGF receptor 3 (VEGFR-3) activation and were mediated through the PI3K-Akt, Erk1/2, and p38 MAPK signaling pathways in relation to the reorganization of the actin cytoskeleton. Our results indicate that endogenous EFs may play a role in lymphangiogenesis in vivo, and VEGFR-3 signaling activation may be involved in the cellular function of LECs driven by EFs.


Assuntos
Linfangiogênese , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Células Endoteliais/metabolismo , Transdução de Sinais
5.
Cell Mol Biol (Noisy-le-grand) ; 69(8): 50-56, 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37715429

RESUMO

The study aimed to explore the expression and function of VEGFRs in normal epidermis and keratinocytes of psoriatic lesions. In this study, the expression and role of VEGFRs in keratinocytes were examined using examples from psoriatic and healthy individuals. The experiment was completed by immunofluorescence analysis, reverse transcription polymerase chain reaction, Western blot, and real-time quantitative RT-PCR after the skin of nonlesional, adjacent, and lesional skin was excised. Observations indicated that in non-lesional psoriatic areas and adjacent lesional areas of the skin of psoriasis patients, the fluorescent signals of VEGFR-1 and VEGFR-2 were strongly labelled with keratinocytes, and in psoriatic lesions, keratinocytes were present throughout the entire thickness of the epidermis, with the exception of the stratum corneum. The distribution of VEGFR-3 in psoriatic nonlesional and adjacent lesional skin was consistent with that in normal epidermis, whereas all layers of the epidermis of psoriatic lesions expressed VEGFR-3. The mRNA expression levels of VEGFR-1,2,3 steadily increased from the normal epidermis to the psoriatic nonlesional, adjacent lesional, and perilesional areas, with the lesional epidermis' keratinocytes exhibiting the greatest levels of mRNA expression. Ca ions upregulate VEGFR-1,2,3 mRNA and protein expression in keratinocytes of nonlesional areas of psoriasis. VEGFRs protein expression and cortical IOD values of psoriatic and normal population cells showed a positive correlation. Hence, in comparison to normal epidermal keratinocytes, psoriatic lesional regions' keratinocytes considerably enhanced their expression of VEGFR-1,2,3 mRNA and protein. The overexpression of VEGFR-1,2,3 in psoriatic lesions may be encouraged by VEGF and Ca þ ions.


Assuntos
Psoríase , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Queratinócitos , Epiderme , Psoríase/genética
6.
Cell Rep ; 42(7): 112777, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37454290

RESUMO

Lymphatic capillaries develop discontinuous cell-cell junctions that permit the absorption of large macromolecules, chylomicrons, and fluid from the interstitium. While excessive vascular endothelial growth factor 2 (VEGFR2) signaling can remodel and seal these junctions, whether and how VEGFR3 can alter lymphatic junctions remains incompletely understood. Here, we use lymphatic-specific Flt4 knockout mice to investigate VEGFR3 signaling in lymphatic junctions. We show that loss of Flt4 prevents specialized button junction formation in multiple tissues and impairs interstitial absorption. Knockdown of FLT4 in human lymphatic endothelial cells results in impaired NOTCH1 expression and activation, and overexpression of the NOTCH1 intracellular domain in Flt4 knockout vessels rescues the formation of button junctions and absorption of interstitial molecules. Together, our data reveal a requirement for VEGFR3 and NOTCH1 signaling in the development of button junctions during postnatal development and may hold clinical relevance to lymphatic diseases with impaired VEGFR3 signaling.


Assuntos
Células Endoteliais , Vasos Linfáticos , Receptor Notch1 , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Linfangiogênese/fisiologia , Vasos Linfáticos/metabolismo , Camundongos Knockout , Transdução de Sinais , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo
7.
Haematologica ; 108(11): 2933-2945, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37317880

RESUMO

Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Animais , Camundongos , Fator C de Crescimento do Endotélio Vascular/uso terapêutico , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Medula Óssea/metabolismo , Antineoplásicos/uso terapêutico , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/uso terapêutico
8.
Cell Rep ; 42(5): 112489, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37167063

RESUMO

Upon recognizing danger signals produced by virally infected neurons, macrophages in the central nervous system (CNS) secrete multiple inflammatory cytokines to accelerate neuron apoptosis. The understanding is limited about which key effectors regulate macrophage-neuron crosstalk upon infection. We have used neurotropic-virus-infected murine models to identify that vascular endothelial growth factor receptor 3 (VEGFR-3) is upregulated in the CNS macrophages and that virally infected neurons secrete the ligand VEGF-C. When cultured with VEGF-C-containing supernatants from virally infected neurons, VEGFR-3+ macrophages suppress tumor necrosis factor α (TNF-α) secretion to reduce neuron apoptosis. Vegfr-3ΔLBD/ΔLBD (deletion of ligand-binding domain in myeloid cells) mice or mice treated with the VEGFR-3 kinase inhibitor exacerbate the severity of encephalitis, TNF-α production, and neuron apoptosis post Japanese encephalitis virus (JEV) infection. Activating VEGFR-3 or blocking TNF-α can reduce encephalitis and neuronal damage upon JEV infection. Altogether, we show that the inducible VEGF-C/VEGFR-3 module generates protective crosstalk between neurons and macrophages to alleviate CNS viral infection.


Assuntos
Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa , Camundongos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Ligantes , Fator A de Crescimento do Endotélio Vascular/metabolismo , Encefalite Japonesa/metabolismo , Encefalite Japonesa/patologia , Vírus da Encefalite Japonesa (Espécie)/metabolismo , Neurônios/metabolismo , Macrófagos/metabolismo
9.
Microvasc Res ; 148: 104546, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37230165

RESUMO

Inflammatory pleuritis often causes pleural effusions, which are drained through lymphatic vessels (lymphatics) in the parietal pleura. The distribution of button- and zipper-like endothelial junctions can identify the subtypes of lymphatics, the initial, pre-collecting, and collecting lymphatics. Vascular endothelial growth factor receptor (VEGFR)-3 and its ligands VEGF-C/D are crucial lymphangiogenic factors. Currently, in the pleura covering the chest walls, the anatomy of the lymphatics and connecting networks of blood vessels are incompletely understood. Moreover, their pathological and functional plasticity under inflammation and the effects of VEGFR inhibition are unclear. This study aimed to learn the above-unanswered questions and immunostained mouse chest walls as whole-mount specimens. Confocal microscopic images and their 3-dimensional reconstruction analyzed the vasculatures. Repeated intra-pleural cavity lipopolysaccharide challenge induced pleuritis, which was also treated with VEGFR inhibition. Levels of vascular-related factors were evaluated by quantitative real-time polymerase chain reaction. We observed the initial lymphatics in the intercostals, collecting lymphatics under the ribs, and pre-collecting lymphatics connecting both. Arteries branched into capillaries and gathered into veins from the cranial to the caudal side. Lymphatics and blood vessels were in different layers with an adjacent distribution of the lymphatic layer to the pleural cavity. Inflammatory pleuritis elevated expression levels of VEGF-C/D and angiopoietin-2, induced lymphangiogenesis and blood vessel remodeling, and disorganized the lymphatic structures and subtypes. The disorganized lymphatics showed large sheet-like structures with many branches and holes inside. Such lymphatics were abundant in zipper-like endothelial junctions with some button-like junctions. The blood vessels were tortuous and had various diameters and complex networks. Stratified layers of lymphatics and blood vessels were disorganized, with impaired drainage function. VEGFR inhibition partially maintained their structures and drainage function. These findings demonstrate anatomy and pathological changes of the vasculatures in the parietal pleura and their potential as a novel therapeutic target.


Assuntos
Vasos Linfáticos , Pleurisia , Camundongos , Animais , Pleura/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vasos Linfáticos/metabolismo , Linfangiogênese , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Inflamação/metabolismo , Pleurisia/metabolismo , Pleurisia/patologia
10.
J Nanobiotechnology ; 21(1): 130, 2023 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-37069646

RESUMO

BACKGROUND: TMVP1 is a novel tumor targeting polypeptide screened by our laboratory with a core sequence of five amino acids LARGR. It specially binds to vascular endothelial growth factor receptor-3 (VEGFR-3), which is mainly expressed on neo-lymphatic vessels in sentinel lymph node (SLN) with tumor metastasis in adults. Here, we prepared a targeted nanoprobe using TMVP1-modified nanomaterials for tumor metastasis SLN imaging. RESULTS: In this study, TMVP1-modified polymer nanomaterials were loaded with the near-infrared (NIR) fluorescent dye, indocyanine green (ICG), to prepare a molecular imaging TMVP1-ICG nanoparticles (NPs) to identify tumor metastasis in SLN at molecular level. TMVP1-ICG-NPs were successfully prepared using the nano-precipitation method. The particle diameter, morphology, drug encapsulation efficiency, UV absorption spectrum, cytotoxicity, safety, and pharmacokinetic properties were determined. The TMVP1-ICG-NPs had a diameter of approximately 130 nm and an ICG loading rate of 70%. In vitro cell experiments and in vivo mouse experiments confirmed that TMVP1-ICG-NPs have good targeting ability to tumors in situ and to SLN with tumor metastasis by binding to VEGFR-3. Effective photothermal therapy (PTT) with TMVP1-ICG-NPs was confirmed in vitro and in vivo. As expected, TMVP1-ICG-NPs improved ICG blood stability, targeted tumor metastasis to SLN, and enhanced PTT/photodynamic (PDT) therapy, without obvious cytotoxicity, making it a promising theranostic nanomedicine. CONCLUSION: TMVP1-ICG-NPs identified SLN with tumor metastasis and were used to perform imaging-guided PTT, which makes it a promising strategy for providing real-time NIR fluorescence imaging and intraoperative PTT for patients with SLN metastasis.


Assuntos
Linfonodo Sentinela , Animais , Camundongos , Linfonodo Sentinela/diagnóstico por imagem , Linfonodo Sentinela/patologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Terapia Fototérmica , Fator A de Crescimento do Endotélio Vascular , Verde de Indocianina/química , Imagem Óptica/métodos , Imagem Molecular/métodos
11.
Sci Immunol ; 8(82): eabq0375, 2023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-37058549

RESUMO

The recent discovery of lymphatic vessels (LVs) in the dura mater, the outermost layer of meninges around the central nervous system (CNS), has opened a possibility for the development of alternative therapeutics for CNS disorders. The vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR3) signaling pathway is essential for the development and maintenance of dural LVs. However, its significance in mediating dural lymphatic function in CNS autoimmunity is unclear. We show that inhibition of the VEGF-C/VEGFR3 signaling pathway using a monoclonal VEGFR3-blocking antibody, a soluble VEGF-C/D trap, or deletion of the Vegfr3 gene in adult lymphatic endothelium causes notable regression and functional impairment of dural LVs but has no effect on the development of CNS autoimmunity in mice. During autoimmune neuroinflammation, the dura mater was only minimally affected, and neuroinflammation-induced helper T (TH) cell recruitment, activation, and polarization were significantly less pronounced in the dura mater than in the CNS. In support of this notion, during autoimmune neuroinflammation, blood vascular endothelial cells in the cranial and spinal dura expressed lower levels of cell adhesion molecules and chemokines, and antigen-presenting cells (i.e., macrophages and dendritic cells) had lower expression of chemokines, MHC class II-associated molecules, and costimulatory molecules than their counterparts in the brain and spinal cord, respectively. The significantly weaker TH cell responses in the dura mater may explain why dural LVs do not contribute directly to CNS autoimmunity.


Assuntos
Vasos Linfáticos , Fator C de Crescimento do Endotélio Vascular , Animais , Camundongos , Células Endoteliais/metabolismo , Linfangiogênese , Doenças Neuroinflamatórias , Transdução de Sinais , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/farmacologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
J Cell Biochem ; 124(5): 674-686, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36922713

RESUMO

Vascular endothelial growth factor receptor 3 (VEGFR3) is expressed in cancer cell lines and exerts a critical role in cancer progression. However, the signaling pathways of VEGFR3 in ovarian cancer cell proliferation remain unclear. This study aimed to demonstrate the signaling pathways of VEGFR3 through the upregulated expression of miR-1236 in ovarian cancer cells. We found that the messenger RNA and protein of VEGFR3 were expressed in the ovarian cancer cell lines, but downregulated after microRNA-1236 (miR-1236) transfection. The inhibition of VEGFR3, using miR-1236, significantly reduced cell proliferation, clonogenic survival, migration, and invasion ability in SKOV3 and OVCAR3 cells (p < 0.01). The flow cytometry results indicated that the rate of apoptotic cells in SKOV3 (38.65%) and OVCAR3 (41.95%) cells increased following VEGFR3 inhibition. Moreover, VEGFR3 stimulation (using a specific ligand, VEGF-CS) significantly increased extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation (p < 0.01), whereas VEGFR3 suppression reduced p-ERK1/2 (67.94% in SKOV3 and 93.52% in OVCAR3) and p-AKT (59.56% in SKOV3 and 78.73% in OVCAR3) compared to the VEGF-CS treated group. This finding demonstrated that miR-1236 may act as an endogenous regulator of ERK1/2 and AKT signaling by blocking the upstream regulator of VEGFR3. Overall, we demonstrated the important role of the miR-1236/VEGFR3 axis in ovarian cancer cell proliferation by regulating the ERK1/2 and AKT signaling that might be an effective strategy against ovarian cancer.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Feminino , Humanos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , 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
13.
Lymphat Res Biol ; 21(4): 372-380, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36880955

RESUMO

Background: Lymphedema is an intractable disease with no curative treatment available. Conservative treatment is the mainstay, and new drug treatment options are strongly needed. The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model. Methods and Results: Male C57BL/6N mice (8-10 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated, and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor receptor-3 (VEGFR-3), vascular endothelial growth factor-C (VEGF-C), and Prospero homeobox 1 (Prox1) on postoperative day 4 was significantly higher in the roxadustat group compared with the control group. Conclusions: Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema through promotion of lymphangiogenesis through the activation of HIF-1α, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.


Assuntos
Linfedema , Inibidores de Prolil-Hidrolase , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Membro Posterior , Linfangiogênese/fisiologia , Linfedema/tratamento farmacológico , Camundongos Endogâmicos C57BL , Inibidores de Prolil-Hidrolase/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
14.
Cells ; 12(4)2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36831193

RESUMO

Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2-/- mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2-/- mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced VEGFR3 expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis.


Assuntos
Linfangiogênese , Fator A de Crescimento do Endotélio Vascular , Camundongos , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Esteroides/metabolismo , Ácidos e Sais Biliares/metabolismo
15.
Cancer Immunol Immunother ; 72(9): 2919-2925, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36763100

RESUMO

Previously, we found that dysfunctional natural killer (NK) cells with low interferon gamma (IFN-γ) were restored in acute myeloid leukemia (AML) by the FLT4 antagonist MAZ51. Here, we developed 12 peptides targeting FLT4 for clinical application and examined whether they restored the frequency of lymphocytes, especially T cells and NK cells, and high IFN-γ expression, as MAZ51 treatment did in our previous study. Although clinical data from using peptides are currently available, peptides targeting FLT4 to modulate immune cells have not been fully elucidated. In this study, we focus on novel peptide 4 (P4) from the intracellular domain of FLT4 because it had dominant negative activity. Similar to MAZ51, high IFN-γ levels were expressed in AML-mononuclear cells exposed to P4. Additionally, T and NK cell levels were restored, as were high IFN-γ levels, in a leukemic environment when P4 was treated. Interestingly, the regulatory T cells were significantly decreased by P4, implying the role of peptide in tumor niche. Overall, we demonstrated the therapeutic value of functionally modulating lymphocytes using a peptide targeting FLT4 and proposed the development of advanced therapeutic approaches against AML by using immune cells.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Células Matadoras Naturais , Interferon gama/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular
16.
Int J Mol Sci ; 24(4)2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36835014

RESUMO

Due to the lack of specific targets, cytotoxic chemotherapy still represents the common standard treatment for triple-negative breast patients. Despite the harmful effect of chemotherapy on tumor cells, there is evidence that treatment could modulate the tumor microenvironment in a way favoring the propagation of the tumor. In addition, the lymphangiogenesis process and its factors could be involved in this counter-therapeutic event. In our study, we have evaluated the expression of the main lymphangiogenic receptor VEGFR3 in two triple-negative breast cancer in vitro models, resistant or not to doxorubicin treatment. The expression of the receptor, at mRNA and protein levels, was higher in doxorubicin-resistant cells than in parental cells. In addition, we confirmed the upregulation of VEGFR3 levels after a short treatment with doxorubicin. Furthermore, VEGFR3 silencing reduced cell proliferation and migration capacities in both cell lines. Interestingly, high VEGFR3 expression was significantly positively correlated with worse survival in patients treated with chemotherapy. Furthermore, we have found that patients with high expression of VEGFR3 present shorter relapse-free survival than patients with low levels of the receptor. In conclusion, elevated VEGFR3 levels correlate with poor survival in patients and with reduced doxorubicin treatment efficacy in vitro. Our results suggest that the levels of this receptor could be a potential marker of meager doxorubicin response. Consequently, our results suggest that the combination of chemotherapy and VEGFR3 blockage could be a potentially useful therapeutic strategy for the treatment of triple-negative breast cancer.


Assuntos
Doxorrubicina , Neoplasias de Mama Triplo Negativas , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Recidiva Local de Neoplasia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Arthritis Rheumatol ; 75(6): 923-936, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36625730

RESUMO

OBJECTIVE: The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease. METHODS: SLS function was assessed in the knees of young (3-month-old) and aged (19-24-month-old) male and female C57BL/6J mice via a newly established in vivo IVIS-dextran imaging approach, which, in addition to histology, was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice. RNA-sequencing of synovial tissue was performed to explore molecular mechanisms of the disease in the mouse knee joints. RESULTS: Results showed that aged mice had impaired SLS function, including decreases in joint clearance (mean T1/2 of signal intensity clearance, 2.8 hours in aged mice versus 0.5 hours in young mice; P < 0.0001), synovial influx (mean ± SD 1.7 ± 0.8% in aged mice versus 4.1 ± 1.9% in young mice; P = 0.0004), and lymph node draining capacity (mean ± SD epifluorescence total radiant intensity ([photons/second]/[µW/cm2 ]) 1.4 ± 0.8 in aged mice versus 3.7 ± 1.2 in young mice; P < 0.0001). RNA-sequencing of the synovial tissue showed that Vegf-c and Vegfr3 signaling genes were decreased in the synovium of aged mice. VEGF-C treatment resulted in improvements in SLS function in aged mice, including increased percentage of signal intensity joint clearance (mean ± SD 63 ± 9% in VEGF-C-treated aged mice versus 52 ± 15% in vehicle-treated aged mice; P = 0.012), increased total articular cartilage cross-sectional area (mean ± SD 0.38 ± 0.07 mm2 in VEGF-C-treated aged mice versus 0.26 ± 0.07 mm2 in vehicle-treated aged mice; P < 0.0001), and decreased percentage of matrix metallopeptidase 13-positive staining area within total synovial area in 22-month-old VEGF-C-treated mice versus 22-month-old vehicle-treated mice (mean ± SD decrease 7 ± 2% versus 4 ± 1%; P = 0.0004). CONCLUSION: SLS function is reduced in the knee joints of aged mice due to decreased VEGF-C/VEGFR-3 signaling. VEGF-C treatment attenuates OA joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR-3 signaling represent novel physiopathologic mechanisms that could potentially be used as therapeutic targets for age-related OA.


Assuntos
Osteoartrite , Fator C de Crescimento do Endotélio Vascular , Camundongos , Masculino , Feminino , Animais , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , RNA/metabolismo
18.
Asian Pac J Cancer Prev ; 24(1): 267-274, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36708576

RESUMO

BACKGROUND: The incidence of oral squamous cell carcinoma (OSCC) is very high in South Asia and Vascular endothelial growth factor (VEGF) is one of the key factors essential for cancer growth. The importance of VEGF-A and VEGF Receptor 2(VEGFR-2) in oral cancer pathophysiology is yet to be decided. Vascular Endothelial Growth Factor A (VEGF-A) is the main factor concerned in angiogenesis in tumors, but its role in Oral Squamous Cell Carcinoma (OSCC) is still debatable. Our study aimed to determine the role of VEGF-A and VEGFR-2 in OSCC. METHODS: Blood from 30 patients with primary OSCC and 1:1 age-sex-matched controls was subjected to qPCR and ELISA to detect VEGF-A gene expression and serum level. Tumors of the 30 patients were investigated for VEGF Receptor-2 (VEGFR-2) expression and were analyzed using Image J software version 1.52 for DAB percentage (DAB-P) area and optical density (OD). RESULTS: VEGF-A relative gene expression among patients was 2.43-fold higher compared to the healthy control group. Well-differentiated had a 1.98-fold increment, while poorly differentiated had a 3.58-fold increment. Serum VEGF-A was significantly elevated among the patients compared to controls (458.7 vs 253.2, p=0.0225). Poorly differentiated had a higher serum VEGF concentration (1262.0±354.7pg/ml) compared with other two. Mean VEGFR-2 DAB-P level in OSCC was 42.41±5.61(p=0.15). Well-differentiated had a DAB-P of 41.20±5.32 while poorly differentiated had DAB-P 46.21±3.78. The mean OD in OSCC was 0.54±0.16. VEGFR-2 OD in well and poorly differentiated OSCC were 0.48±0.12 and 0.68±0.17, respectively. CONCLUSIONS: VEGF-A gene expression, serum levels, and tissue VEGFR-2 levels correlated linearly with the stage and grade of the tumor. This study justifies the value of VEGF-A as a potential biomarker in OSCC in early detection of OSCC. More studies are needed to accept the use of VEGF-A.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/irrigação sanguínea , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias Bucais/metabolismo , Sri Lanka , Biomarcadores , Fatores de Crescimento do Endotélio Vascular , Neovascularização Patológica/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Biogerontology ; 24(5): 727-740, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-36680698

RESUMO

Aging-related skin diseases are gradually increasing due to the imbalance of cutaneous homeostasis in the aging population. Skin aging-induced inflammation promotes systemic inflammation and may lead to whole-body aging. Lymphatic vessels play an important role in maintaining fluid and homeostasis balance. In intrinsically aged skin, the number of lymphatic vessels decrease and their functions decline, which is related to the reduced adhesion junctions between lymphatic endothelial cells, particularly VE-cadherin. VEGFC/VEGFR-3 signal pathway plays an important role in remodeling and expansion of lymphatic vessels; the downregulation of this pathway contributes to the dysfunction of lymphatic vessels. Meanwhile, we proposed some additional mechanisms. Decline of the pumping activity of lymphatic vessels might be related to age-related changes in extracellular matrix, ROS increase, and eNOS/iNOS disturbances. In extrinsically aged skin, the hyperpermeability of lymphatic vessels results from a decrease in endothelial-specific tight junction molecules, upregulation of VEGF-A, and downregulation of the VEGFC/VEGFR-3 signaling pathway. Furthermore, some of the Phyto therapeutics could attenuate skin aging by modulating the lymphatic vessels. This review summarized the lymphatic vessel dysfunction in skin aging and anti-aging strategies based on lymphatic vessel modulation.


Assuntos
Vasos Linfáticos , Envelhecimento da Pele , Humanos , Idoso , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais , Vasos Linfáticos/metabolismo , Transdução de Sinais/fisiologia , Inflamação/metabolismo
20.
Birth Defects Res ; 115(5): 563-571, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36538874

RESUMO

BACKGROUND: Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. CASES: In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. CONCLUSION: Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.


Assuntos
Hidropisia Fetal , Linfedema , Humanos , Gravidez , Feminino , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Hibridização Genômica Comparativa , Linfedema/congênito , Linfedema/diagnóstico , Linfedema/genética , Ultrassonografia Pré-Natal , Mutação , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
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