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BACKGROUND: Accumulating evidence suggests that prostaglandin E2, an arachidonic acid (AA) metabolite, enhances lymphangiogenesis in response to inflammation. However, thromboxane A2 (TXA2), another AA metabolite, is not well known. Thus, this study aimed to determine the role of thromboxane prostanoid (TP) signaling in lymphangiogenesis in secondary lymphedema. METHODS AND RESULTS: Lymphedema was induced by the ablation of lymphatic vessels in mouse tails. Compared with wild-type mice, tail lymphedema in Tp-deficient mice was enhanced, which was associated with suppressed lymphangiogenesis as indicated by decreased lymphatic vessel area and pro-lymphangiogenesis-stimulating factors. Numerous macrophages were found in the tail tissues of Tp-deficient mice. Furthermore, the deletion of TP in macrophages increased tail edema and decreased lymphangiogenesis and pro-lymphangiogenic cytokines, which was accompanied by increased numbers of macrophages and gene expression related to a pro-inflammatory macrophage phenotype in tail tissues. In vivo microscopic studies revealed fluorescent dye leakage in the lymphatic vessels in the wounded tissues. CONCLUSIONS: The results suggest that TP signaling in macrophages promotes lymphangiogenesis and prevents tail lymphedema. TP signaling may be a therapeutic target for improving lymphedema-related symptoms by enhancing lymphangiogenesis.
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Vasos Linfáticos , Linfedema , Ratones , Animales , Linfangiogénesis , Prostaglandinas/metabolismo , Tromboxanos/metabolismo , Vasos Linfáticos/metabolismo , Macrófagos/metabolismo , Linfedema/genética , Linfedema/metabolismoRESUMEN
The process of gastric ulcer healing includes cell migration, proliferation, angiogenesis and re-epithelialization. Platelets contain angiogenesis stimulating factors that induce angiogenesis. Thromboxane A2 (TXA2 ) not only induces platelet activity but also angiogenesis. This study investigated the role of TXA2 in gastric ulcer healing using TXA2 receptor knockout (TPKO) mice. Gastric ulcer healing was suppressed by treatment with the TXA2 synthase inhibitor OKY-046 and the TXA2 receptor antagonist S-1452 compared with vehicle-treated mice. TPKO showed delayed gastric ulcer healing compared with wild-type mice (WT). The number of microvessels and CD31 expression were lower in TPKO than in WT mice, and TPKO suppressed the expression of transforming growth factor beta (TGF-ß) and vascular endothelial growth factor A (VEGF-A) in areas around gastric ulcers. Immunofluorescence assays showed that TGF-ß and VEGF-A co-localized with platelets. Gastric ulcer healing was significantly reduced in WT mice transplanted with TPKO compared with WT bone marrow. These results suggested that TP signalling on platelets facilitates gastric ulcer healing through TGF-ß and VEGF-A.
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Neovascularización Patológica/metabolismo , Úlcera Gástrica/tratamiento farmacológico , Tromboxanos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Ratones Endogámicos C57BL , Activación Plaquetaria/efectos de los fármacos , Prostaglandinas/farmacología , Receptores de Tromboxanos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Úlcera Gástrica/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
AIMS: Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation. METHODS: This study consisted of single-dose and multiple-dose tests with a dose-escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single-dose test. Patients received test tablets once daily for 14 days in multiple-dose test. We assessed pharmacokinetic-dose proportionality, levels of serum high- and low-density lipoprotein cholesterol and plasma 7α-hydroxy-4-cholesten-3-one (C4), food effect and sex-specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated. RESULTS: Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371-0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple-dose test, elobixibat reduced low-density lipoprotein cholesterol and increased C4 whilst unaltering high-density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild. CONCLUSIONS: Elobixibat should be taken before breakfast. Once-daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.
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Proteínas Portadoras/antagonistas & inhibidores , Estreñimiento/tratamiento farmacológico , Dipéptidos/farmacología , Glicoproteínas de Membrana/antagonistas & inhibidores , Tiazepinas/farmacología , Administración Oral , Adulto , Proteínas Portadoras/metabolismo , Colestenonas/sangre , LDL-Colesterol/sangre , Enfermedad Crónica/tratamiento farmacológico , Estreñimiento/sangre , Estreñimiento/patología , Estudios Cruzados , Defecación/efectos de los fármacos , Dipéptidos/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Interacciones Alimento-Droga , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Íleon/patología , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Placebos/administración & dosificación , Placebos/efectos adversos , Factores Sexuales , Comprimidos , Tiazepinas/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor- ß1 (TGF-ß1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80+ cells expressing TGF-ß1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO-BM)âWT showed suppressed formation of liver metastasis compared with WT-BMâWT. However, the formation of metastasis was further suppressed in WT-BMâAT1aKO compared with AT1aKO-BMâWT. In addition, accumulated F4/80+ cells in the liver metastasis were not BM-derived F4/80+ cells, but mainly resident hepatic F4/80+ cells, and these resident hepatic F4/80+ cells were positive for TGF-ß1. Angiotensin II enhanced TGF-ß1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF-ß1+ F4/80+ cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-ß1 through AT1a signaling.
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Neoplasias Colorrectales/metabolismo , Macrófagos del Hígado/fisiología , Neoplasias Hepáticas Experimentales/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Proteínas Angiogénicas/metabolismo , Angiotensina II/fisiología , Animales , Línea Celular Tumoral , Colágeno Tipo I/metabolismo , Neoplasias Colorrectales/patología , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/secundario , Masculino , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Secondary lymphedema commonly arises as a complication of cancer surgery and radiation treatment; however, the underlying mechanisms are poorly understood. Receptor activity-modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor to generate the receptor for calcitonin gene-related peptide. The present study examined whether RAMP1 plays a role in increased lymphangiogenesis during secondary lymphedema. METHODS: A model of lymphedema was generated by surgical removal of pre-existing lymphatic vessels from the subcutaneous tissue on the tails of RAMP1-deficient (RAMP1-/-) mice and their wild-type (WT) counterparts. The maximum diameter of the tail, lymphangiogenesis, and macrophage recruitment were then examined. RESULTS: Compared with that in WT mice, lymphedema in the tails in RAMP1-/- mice was sustained, with suppressed lymphangiogenesis and reduced expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 at the distal edge of the lesions. The newly formed lymphatic vessels in RAMP1-/- mice were dilated, with impaired lymphatic flow. RAMP1 was expressed by macrophages recruited into edematous tail tissues distal to the wound. The number of macrophages in RAMP1-/- mice was higher than that in WT mice. Expression of messenger RNA encoding M1 macrophage-related genes, including tumor necrosis factor-α and interleukin-1, was higher in RAMP1-/- mice than in WT mice, whereas expression of messenger RNA encoding M2 macrophage genes, including interleukin-10, was lower. CONCLUSIONS: RAMP1 signaling improves lymphedema and accelerates lymphangiogenesis associated with reduced recruitment of pro-inflammatory macrophages.
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Linfangiogénesis/fisiología , Linfedema/metabolismo , Complicaciones Posoperatorias/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Animales , Biomarcadores/metabolismo , Linfedema/etiología , Linfedema/fisiopatología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complicaciones Posoperatorias/fisiopatología , Proteína 1 Modificadora de la Actividad de Receptores/deficiencia , Transducción de SeñalRESUMEN
BACKGROUND: Thromboxane A synthase (TXAS) is the enzyme that converts the arachidonic acid derivative prostaglandin H2 to thromboxane A2 (TXA2). TXA2 induces platelet aggregation, vasoconstriction, and proliferation. TXAS and TXA2 receptors or thromboxane prostanoid (TP) receptors are elevated in numerous cardiovascular and inflammatory diseases. Platelets contain numerous angiogenesis stimulating factors. However, the involvement of TXAS on recovery from an ischemic condition is not well understood. We hypothesized that the TXAS-TXA2-TP receptor axis would induce blood flow recovery by platelet activation. MATERIAL AND METHODS: The model of hindlimb ischemia was made by the right femoral artery ligation. The blood flow was estimated by laser Doppler images. Angiogenesis was estimated by the plasma level of the vascular endothelial growth factor and the stromal cell-derived factor-1 and by immunofluorescence analysis against CD31 and P-selectin glycoprotein ligand-1 (PSGL-1). RESULTS: In wild-type mice, blood flow recovery was enhanced by treatment with murine TXAS-overexpressing fibroblasts (C57-mTXAS) compared with empty vector- (EV) treated fibroblasts (C57-EV). Compared with C57-EV-treated mice, activated platelets (P-selectin(+) platelets) and plasma levels of vascular endothelial growth factor and stromal cell-derived factor-1 were increased in C57-mTXAS-treated mice. The enhanced-blood flow recovery by C57-mTXAS treatment was suppressed in the TP knockout mice (TP(-/-)). The expression of PSGL-1 in endothelial cells around the ischemic area was enhanced by C57-mTXAS treatment in wild-type but not in TP(-/-). CONCLUSIONS: These results indicated that local administration of C57-mTXAS-induced angiogenesis by activated platelets that bind to PSGL-1 on ischemic endothelial cells.
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Fármacos Cardiovasculares/uso terapéutico , Miembro Posterior/irrigación sanguínea , Isquemia/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Tromboxano-A Sintasa/uso terapéutico , Animales , Biomarcadores/metabolismo , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacología , Línea Celular , Arteria Femoral/cirugía , Fibroblastos/enzimología , Fibroblastos/trasplante , Miembro Posterior/diagnóstico por imagen , Miembro Posterior/metabolismo , Isquemia/diagnóstico por imagen , Isquemia/metabolismo , Flujometría por Láser-Doppler , Ligadura , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Fisiológica/fisiología , Activación Plaquetaria/fisiología , Flujo Sanguíneo Regional/fisiología , Tromboxano A2/metabolismo , Tromboxano-A Sintasa/metabolismo , Tromboxano-A Sintasa/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Compensatory lung growth models have been widely used to investigate alveolization because the remaining lung can be kept intact and volume loss can be controlled. Vascular endothelial growth factor (VEGF) plays an important role in blood formation during lung growth and repair, but the precise mechanisms involved are poorly understood; therefore, the aim of this study was to investigate the role of VEGF signaling in compensatory lung growth. After left pneumonectomy, the right lung weight was higher in VEGF transgenic mice than wild-type (WT) mice. Compensatory lung growth was suppressed significantly in mice injected with a VEGF neutralizing antibody and in VEGF receptor-1 tyrosine kinase-deficient mice (TK(-/-) mice). The mobilization of progenitor cells expressing VEGFR1(+) cells from bone marrow and the recruitment of these cells to lung tissue were also suppressed in the TK(-/-) mice. WT mice transplanted with bone marrow from TK(-/-)transgenic GFP(+) mice had significantly lower numbers of GFP(+)/aquaporin 5(+), GFP(+)/surfactant protein A(+), and GFP(+)/VEGFR1(+) cells than WT mice transplanted with bone marrow from WTGFP(+) mice. The GFP(+)/VEGFR1(+) cells also co-stained for aquaporin 5 and surfactant protein A. Overall, these results suggest that VEGF signaling contributes to compensatory lung growth by mobilizing VEGFR1(+) cells.
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Pulmón/metabolismo , Pulmón/fisiología , Neumonectomía , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Células de la Médula Ósea , Citocinas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Pulmón/química , Pulmón/cirugía , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Tamaño de los Órganos/fisiología , Proteínas Tirosina Quinasas/metabolismo , Alveolos Pulmonares/citología , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
The spatial relationships between brain and braincase represent a major topic in surgery and evolutionary neuroanatomy. In paleoneurology, neurocranial landmarks are often used as references for brain areas. In this study, we analyze the variation and covariation of midsagittal brain and skull coordinates in a sample of adult modern humans in order to demonstrate spatial associations between hard and soft tissues. The correlation between parietal lobe size and parietal bone size is very low, and there is a marked individual variation. The distances between lobes and bones are partially influenced by the dimensions of the parietal lobes. The main pattern of morphological variability among individuals, associated with the size of the precuneus, apparently does not influence the position of the neurocranial sutures. Therefore, variations in precuneal size modify the distance between the paracentral lobule and bregma, and between the parietal lobe and lambda. Hence, the relative position of the cranial and cerebral landmarks can change as a function of the parietal dimensions. The slight correlation and covariation among these elements suggests a limited degree of spatial integration between soft and hard tissues. Therefore, although the brain influences the cranial size and shape during morphogenesis, the specific position of the cerebral components is sensitive to multiple effects and local factors, without a strict correspondence with the bone landmarks. This absence of correspondent change between brain and skull boundaries suggests caution when making inferences about the brain areas from the position of the cranial sutures. The fact that spatial relationships between cranial and brain areas may vary according to brain proportions must be considered in paleoneurology, when brain anatomy is inferred from cranial evidence.
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Hueso Parietal/anatomía & histología , Lóbulo Parietal/anatomía & histología , Adulto , Puntos Anatómicos de Referencia/anatomía & histología , Evolución Biológica , Femenino , Fósiles , Humanos , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Adulto JovenRESUMEN
BACKGROUND: Recently, the Japanese Respiratory Society (JRS) proposed using lung age (LA) as an indicator of lung function; however, reports regarding the association of LA with the risk of postoperative readmission within 90 d after surgical treatment for non-small cell lung cancer (NSCLC) are limited. Here, we analyze the clinical relationship between LA and readmission within 90 d after surgical treatment for NSCLC. METHODS: A total of 979 patients underwent curative resections for NSCLC from January 2000-September 2012 at the Kitasato University Hospital. We selected patients who required readmission because of surgical complications within 90 d of surgery and retrospectively analyzed various clinical data. LA was calculated based on the formula given by the Japanese Respiratory Society, which relies on preoperative respiratory function. We also calculated the age gap (AG) between the calculated LA and the true age (TA). RESULTS: There were 216 patients who needed to be readmitted within 90 d of surgery, 33 (3%) of whom were hospitalized for surgical complications. Twenty-four patients (73%) had respiratory complications, and 7 patients (21%) died. There were significant differences between the readmitted and no readmitted patients in terms of preoperative factors, such as gender, LA, AG, smoking status, and smoking index (P < 0.05). In addition, there were significant differences in intraoperative blood loss, postoperative complications, histologic type, duration of hospitalization, and hospitalization after surgery (P < 0.05). Multivariate analysis using logistic regression indicated that LA, AG, blood loss, and postoperative complications were independent factors that predicted readmission. Additionally, the 5-y survival rates were 78% and 44% for the no readmitted and readmitted groups, respectively (P < 0.001). CONCLUSIONS: The AG between TA and LA was significantly associated with postoperative complications and remained an independent predictive factor after multiple regressions. LA was shown to be a useful factor for predicting the risk of surgery-related readmission within 90 d after surgery for NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Readmisión del Paciente/estadística & datos numéricos , Pruebas de Función Respiratoria , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Comorbilidad , Femenino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
OBJECTIVES: We describe a new computer reconstruction to obtain complete anatomical information of the ecto- and endocranium from the imperfectly preserved skull of the Neanderthal Amud 1. MATERIALS AND METHODS: Data were obtained from computed tomography scans of the fossil cranium. Adhesive and plaster were then virtually removed from the original specimen, and the fragments comprising the fossil cranium were separated. These fragments were then mathematically reassembled based on the smoothness of the joints. Both sides of the cranium were reassembled separately, and then aligned based on bilateral symmetry and the distance between the mandibular fossae obtained from the associated mandible. The position of the isolated maxilla was determined based on the position of the mandible that was anatomically articulated to the mandibular fossae. To restore missing basicranial and damaged endocranial regions, the cranium of Forbes' Quarry 1 was warped onto that of La Chapelle-aux-Saints 1, and the resulting composite Neanderthal cranium was then warped onto the reconstructed Amud 1 by an iterative thin-plate spline deformation. RESULTS: Comparison of the computer reconstruction with the original indicated that the newly reconstructed Amud 1 cranium was slightly shorter and wider in the anteroposterior and mediolateral directions, respectively, suggesting that it was relatively more brachycephalic. The endocranial volume was estimated to be 1,736 cm3 , which was quite similar to the original estimated value of 1,740 cm3 . DISCUSSION: This new computer reconstruction enables not only measurement of new cranial metrics, but also inclusion of the Amud 1 specimen in three-dimensional geometric morphometric analyses that were previously difficult due to its incompleteness. Am J Phys Anthropol 158:185-197, 2015. © 2015 Wiley Periodicals, Inc.
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Angiotensin II is involved in tumor growth; however, the precise mechanism is not known. Platelets also contribute to tumor growth, and angiotensin II type 1 receptor (AT1) is expressed on the platelet surface. We hypothesized that interaction of platelets with tumor cells through AT1 receptor signaling promotes tumor metastasis. B16F1 melanoma cells were intravenously injected into Agtr1a knockout mice (AT1a(-/-)) and wild-type littermates (WT); the AT1a(-/-) mice exhibited a reduction in lung colonies. Angiotensin II induced expression of P-selectin on platelets in WT but not in AT1a(-/-) mice. A selective P-selectin neutralizing antibody decreased lung colony numbers in WT but not in AT1a(-/-) mice. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) receptor in platelets at metastatic locus were lower in AT1a(-/-) mice. Treatment of neutralizing antibodies against VEGF and CXCR4 decreased lung colony numbers in WT but not in AT1a(-/-) mice. In AT1a(-/-) mice, and both mobilization of progenitor cells expressing CXCR4(+)VEGFR1(+) cells from bone marrow and their recruitment to lung tissues were suppressed. These results suggest that AT1A signaling plays a critical role in tumor metastasis through P-selectin-mediated interactions of platelets with tumor and endothelial cells and through the AT1A signaling-dependent production of VEGF and SDF-1, which may be involved in mobilization of CXCR4(+)VEGFR1(+) cells.
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Plaquetas/patología , Comunicación Celular , Células Endoteliales de la Vena Umbilical Humana/patología , Neoplasias Pulmonares/secundario , Selectina-P/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal , Angiotensina II/farmacología , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Trasplante de Médula Ósea , Comunicación Celular/efectos de los fármacos , Quimiocina CXCL12/sangre , Ensayo de Unidades Formadoras de Colonias , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Adhesividad Plaquetaria/efectos de los fármacos , Recuento de Plaquetas , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND/AIM: Intestinal lymphatic vessels (lacteals) play a critical role in the absorption and transport of dietary lipids into the circulation. Calcitonin gene-related peptide and receptor activity-modifying protein 1 (RAMP1) are involved in lymphatic vessel growth. This study aimed to examine the role of RAMP1 signaling in lacteal morphology and function in response to a high-fat diet (HFD). MATERIALS AND METHODS: RAMP1 deficient (RAMP1-/-) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 8 weeks. RESULTS: RAMP1-/- mice fed a HFD had increased body weights compared to WT mice fed a HFD, which was associated with high levels of total cholesterol, triglycerides, and glucose. HFD-fed RAMP1-/- mice had shorter and wider lacteals than HFD-fed WT mice. HFD-fed RAMP1-/- mice had lower levels of lymphatic endothelial cell gene markers including vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vascular growth factor VEGF-C than HFD-fed WT mice. The concentration of an absorbed lipid tracer in HFD-fed RAMP1-/- mice was higher than that in HFD-fed WT mice. The zipper-like continuous junctions were predominant in HFD-fed WT mice, while the button-like discontinuous junctions were predominant in HFD-fed RAMP1-/- mice. CONCLUSION: Deletion of RAMP1 signaling suppressed lacteal growth and VEGF-C/VEGFR3 expression but accelerated the uptake and transport of dietary fats through discontinuous junctions of lacteals, leading to excessive obesity. Specific activation of RAMP1 signaling may represent a target for the therapeutic management of diet-induced obesity.
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Vasos Linfáticos , Factor C de Crecimiento Endotelial Vascular , Ratones , Animales , Factor A de Crecimiento Endotelial Vascular , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Obesidad/genética , Obesidad/metabolismo , Vasos Linfáticos/metabolismo , Grasas de la Dieta , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Background: Craniosynostosis, a common congenital anomaly, results from premature fusion of the cranial sutures. One of the forms of craniosynostosis is premature fusion of the metopic suture, referred to as trigonocephaly, but the diagnosis of metopic suture synostosis remains controversial. The purpose of this study was to clarify, using geometric morphometric analysis, if a metopic ridge alone observed in cases of mild trigonocephaly represents a pathological phenomenon. Methods: Three different cranial morphologies were compared among patients up to 2 years old who were categorized into the true group, the mild group, and the normal group, based on the presence or absence of specific symptoms, history of cranioplasty for trigonocephaly, or lack of any abnormality on computed tomography. Using the obtained computed tomography images, 235 anatomical landmarks and semi-landmarks were plotted on the entire cranial surface for analysis of neurocranial morphology, and the cranial shapes represented by landmarks were analyzed using geometric morphometrics. Principal components of shape variations among specimens were then computed, based on the variance-covariance matrix of the Procrustes residuals of all specimens, and statistically analyzed. Results: The principal component analyses of the variations in endocranial shape, frontal bone shape, and occipital bone shape did not show any significant differences in cranial morphology between mild trigonocephaly and normal skulls; however, true trigonocephaly was found to differ significantly from mild trigonocephaly and normal skulls. Conclusions: These findings suggest that in assessments of cranial morphology, the presence of a ridge alone cannot be diagnosed as fundamentally pathological, and may represent normal morphology.
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Angiogenesis, the formation of new blood vessels from the preexistent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatory drugs that suppress prostanoid biosynthesis are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Accumulated results obtained from prostanoid receptor knockout mice indicate that a prostaglandin E-type receptor signaling EP3 in the host microenvironment is critical in tumor angiogenesis inducing vascular endothelial growth factor A (VEGF-A). Further, lymphangiogenesis was also enhanced by EP signaling via VEGF-C/D inductions in pathological settings. These indicate the importance of EP receptor to facilitate angiogenesis and lymphangiogenesis in vivo. Prostanoids act beyond their commonly understood activities in smooth muscle contraction and vasoactivity, both of which are quick responses elicited within several seconds on stimulations. Prostanoid receptor signaling will be a potential therapeutic target for disease conditions related to angiogenesis and lymphangiogenesis.
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BACKGROUND/AIM: The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx. MATERIALS AND METHODS: RAMP1 deficient (RAMP1-/-) and wild-type (WT) mice were subjected to PHx. RESULTS: RAMP1-/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67+ hepatocytes and hepatic trophic growth factors. Additionally, RAMP1-/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67+ hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group. CONCLUSION: The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx.
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Hepatectomía , Regeneración Hepática , Ratones Noqueados , Neovascularización Fisiológica , Proteína 1 Modificadora de la Actividad de Receptores , Transducción de Señal , Animales , Regeneración Hepática/fisiología , Hepatectomía/métodos , Ratones , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/genética , Hígado/metabolismo , Hígado/irrigación sanguínea , Hígado/cirugía , Hepatocitos/metabolismo , Masculino , AngiogénesisRESUMEN
The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.
Asunto(s)
Quimiocinas CXC/metabolismo , Citocinas/sangre , Neovascularización Fisiológica , Receptores CXCR4/metabolismo , Regeneración , Células Madre/fisiología , Animales , Plaquetas/metabolismo , Quimiocina CXCL12 , Quimiocinas CXC/genética , Humanos , Isquemia/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CXCR4/genética , Factor de Células Madre/metabolismo , Trombocitopenia/metabolismo , Trombopoyetina/sangre , Trombopoyetina/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The liver displays a remarkable regenerative capacity in response to acute liver injury. In addition to the proliferation of hepatocytes during liver regeneration, non-parenchymal cells, including liver macrophages, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) play critical roles in liver repair and regeneration. Liver ischemia-reperfusion injury (IRI) is a major cause of increased liver damage during liver resection, transplantation, and trauma. Impaired liver repair increases postoperative morbidity and mortality of patients who underwent liver surgery. Successful liver repair and regeneration after liver IRI requires coordinated interplay and synergic actions between hepatic resident cells and recruited cell components. However, the underlying mechanisms of liver repair after liver IRI are not well understood. Recent technological advances have revealed the heterogeneity of each liver cell component in the steady state and diseased livers. In this review, we describe the progress in the biology of liver non-parenchymal cells obtained from novel technological advances. We address the functional role of each cell component in response to liver IRI and the interactions between diverse immune repertoires and non-hematopoietic cell populations during the course of liver repair after liver IRI. We also discuss how these findings can help in the design of novel therapeutic approaches. Growing insights into the cellular interactions during liver IRI would enhance the pathology of liver IRI understanding comprehensively and further develop the strategies for improvement of liver repair.
RESUMEN
AIMS: Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs. METHODS AND RESULTS: Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice, 6-8 weeks old, were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-ß (TGF-ß) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1-/- mice. Recovery from ischaemia was significantly suppressed in Ep4-/- mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-ß were suppressed in Ep4-/- mice. Moreover, the number of accumulated FoxP3+ cells in ischaemic tissue was diminished in Ep4-/- mice compared with that in Ep4+/+ mice. CONCLUSION: These findings suggested that mPGES-1/PGE2 induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease.
Asunto(s)
Dinoprostona , Linfocitos T Reguladores , Ratones , Masculino , Animales , Prostaglandina-E Sintasas/genética , Prostaglandina-E Sintasas/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacología , Linfocitos T Reguladores/metabolismo , Ratones Noqueados , Isquemia/genética , Factor de Crecimiento Transformador beta , Factores de Transcripción Forkhead/genéticaRESUMEN
Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A2 (TXA2) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WTâWT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA2 receptor)deficient (TP/) mice into TP/ mice (TP/âTP/), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of proangiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WTâWT mice. Furthermore, TP/âTP/ mice had a higher number of F4/80+ cells than that of WTâWT mice, with increased expression of genes related to the antiinflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)derived macrophages, the levels of VEGFA, VEGFC, and VEGFD decreased in a TPdependent manner. Furthermore, TP signaling affected the polarization of cultured BMderived macrophages to the antiinflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.
Asunto(s)
Endometriosis , Prostaglandinas , Receptores de Tromboxano A2 y Prostaglandina H2 , Animales , Femenino , Ratones , Ácido Araquidónico , Dinoprostona , Neovascularización Patológica/genética , Tromboxanos , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismoRESUMEN
Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via specific receptors. Angiogenesis is defined as the formation of new blood vessels from pre-existing vascular beds and is a critical component of pathological conditions, including inflammation and cancer. Lymphatic vessels play crucial roles in the regulation of interstitial fluid, immune surveillance, and the absorption of dietary fat from the intestine; and they are also involved in the pathogenesis of various diseases. Similar to angiogenesis, lymphangiogenesis, the formation of new lymphatic vessels, is a critical component of pathological conditions. The TP-dependent accumulation of platelets in microvessels has been reported to enhance angiogenesis under pathological conditions. Although the roles of some growth factors and cytokines in angiogenesis and lymphangiogenesis have been well characterized, accumulating evidence suggests that TX induces the production of proangiogenic and prolymphangiogenic factors through the activation of adenylate cyclase, and upregulates angiogenesis and lymphangiogenesis under disease conditions. In this review, we discuss the role of TX as a regulator of angiogenesis and lymphangiogenesis, and its emerging importance as a therapeutic target.