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1.
Nat Commun ; 15(1): 221, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177096

RESUMEN

Lymphedema (LD) is characterized by the accumulation of interstitial fluid, lipids and inflammatory cell infiltrate in the limb. Here, we find that LD tissues from women who developed LD after breast cancer exhibit an inflamed gene expression profile. Lipidomic analysis reveals decrease in specialized pro-resolving mediators (SPM) generated by the 15-lipoxygenase (15-LO) in LD. In mice, the loss of SPM is associated with an increase in apoptotic regulatory T (Treg) cell number. In addition, the selective depletion of 15-LO in the lymphatic endothelium induces an aggravation of LD that can be rescued by Treg cell adoptive transfer or ALOX15-expressing lentivector injections. Mechanistically, exogenous injections of the pro-resolving cytokine IFN-ß restores both 15-LO expression and Treg cell number in a mouse model of LD. These results provide evidence that lymphatic 15-LO may represent a therapeutic target for LD by serving as a mediator of Treg cell populations to resolve inflammation.


Asunto(s)
Araquidonato 15-Lipooxigenasa , Linfedema , Humanos , Ratones , Femenino , Animales , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 15-Lipooxigenasa/metabolismo , Inflamación/metabolismo , Citocinas/metabolismo , Linfocitos T Reguladores/metabolismo
2.
Microvasc Res ; 89: 25-33, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23747987

RESUMEN

Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno-associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies.


Asunto(s)
Proteínas Portadoras/metabolismo , Regulación Neoplásica de la Expresión Génica , Linfangiogénesis/fisiología , Proteínas de la Membrana/metabolismo , Neovascularización Patológica , Factor Plaquetario 4/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Colágeno/química , ADN Complementario/metabolismo , Progresión de la Enfermedad , Combinación de Medicamentos , Endostatinas/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Laminina/química , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante de Neoplasias , Neoplasias/irrigación sanguínea , Proteoglicanos/química , Proteínas Recombinantes/metabolismo
4.
Circ Res ; 94(10): 1301-9, 2004 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-15073041

RESUMEN

Both 17beta-estradiol (E2) and fibroblast growth factor-2 (FGF2) stimulate angiogenesis and endothelial cell migration and proliferation. The first goal of this study was to explore the potential link between this hormone and this growth factor. E2-stimulated angiogenesis in SC Matrigel plugs in Fgf2+/+ mice, but not in Fgf2-/- mice. Cell cultures from subcutaneous Matrigel plugs demonstrated that E2 increased both migration and proliferation in endothelial cells from Fgf2+/+ mice, but not from in Fgf2-/- mice. Several isoforms of fibroblast growth factor-2 (FGF2) are expressed: the low molecular weight 18-kDa protein (FGF2lmw) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2hmw) remains intranuclear, but their role is mainly unknown. The second goal of this study was to explore the respective roles of FGF2 isoforms in the effects of E2. We thus generated mice deficient only in the FGF2lmw (Fgf2lmw-/-). E2 stimulated in vivo angiogenesis and in vitro migration in endothelial cells from Fgf2lmw-/- as it did in Fgf2+/+ mice. E2 increased FGF2hmw protein abundance in endothelial cell cultures from Fgf2+/+ and Fgf2lmw-/- mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2hmw partner. This is the first report for a physiological role for the intracellular FGF2hmw found to mediate the effect of E2 on endothelial cell migration via an intracrine action.


Asunto(s)
Endotelio Vascular/fisiología , Estradiol/farmacología , Factor 2 de Crecimiento de Fibroblastos/fisiología , Neovascularización Fisiológica , Animales , División Celular , Movimiento Celular , Células Cultivadas , Endotelio Vascular/citología , Receptor alfa de Estrógeno , Factor 2 de Crecimiento de Fibroblastos/genética , Ratones , Ratones Noqueados , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Receptores de Estrógenos/fisiología , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal
6.
Atherosclerosis ; 166(1): 41-8, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12482549

RESUMEN

The mechanisms that mediate the atheroprotective properties of estrogens remain obscure. In the present study, we evaluated the involvement of the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) in the atheroprotective effect of estrogens in murine models evaluating early steps of atherosclerosis. First, we studied the effect of 17 beta-estradiol (E2) administration for 12 weeks on fatty streak constitution at the root aorta of ovariectomized female mice deficient in apolipoprotein E (apoE) alone or deficient in both apoE and either P-selectin or ICAM-1. Compared with respective placebo groups, E2 significantly prevented the development of fatty streak, to a similar extent in all three genotypes (-70.0% in apoE(-/-), -77.4% in apoE(-/-) P-selectin(-/-), and -77.1% in apoE(-/-) ICAM-1(-/-)). Second, the endothelial expression of VCAM-1 at the root aorta was assessed by immunohistochemistry in either placebo or E2-treated ovariectomized C57BL/6 female mice fed an atherogenic diet. Compared with placebo, E2 treatment resulted in a 31.8% decrease of VCAM-1 endothelial expression at this lesion-prone site (P=0.03). These results demonstrate that P-selectin and ICAM-1 are not involved in the atheroprotective effect of estrogens, and suggest that VCAM-1 could play a role in this process.


Asunto(s)
Apolipoproteínas E/deficiencia , Arteriosclerosis/metabolismo , Estradiol/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Selectina-P/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Animales , Apolipoproteínas E/genética , Arteriosclerosis/patología , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Molécula 1 de Adhesión Celular Vascular/efectos de los fármacos
7.
Eur J Endocrinol ; 150(2): 113-7, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14763907

RESUMEN

Numerous epidemiological as well as experimental studies have suggested that estradiol (E2) prevents atherosclerosis development. However two controlled prospective and randomized studies in women using hormone replacement therapy (HRT) did not confirm this beneficial effect. We then decided to use mouse models of atherosclerosis to define the possible mechanisms involved and the reasons for the discrepancy. We have shown that, although serum cholesterol decreases, this influence on lipid metabolism is negligible. Surprisingly, E2 induces an inflammatory-immune response towards a T helper cell (Th1) profile with increasing interferon-gamma production that could destabilize atheromatous plaques, and could account for the increase in the frequency of cardiovascular events in women undergoing HRT. At the level of the endothelium, E2 induces an increase in nitric oxide (NO) biodisponibility, but this phenomenon does not concern the development of fatty streaks. Nevertheless, the atheroprotective effect is apparently mediated at the level of the endothelium by a mechanism that has still to be characterized in molecular terms. These new acquisitions constitute a basis for new pharmacological developments allowing the prevention of deleterious effects and preserving the beneficial ones.


Asunto(s)
Arteriosclerosis/fisiopatología , Endotelio Vascular/fisiopatología , Estradiol/metabolismo , Animales , Arteriosclerosis/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/fisiopatología , Ratones , Ratones Noqueados , Células TH1/fisiología
8.
Oncogene ; 32(17): 2150-60, 2013 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-22733133

RESUMEN

The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53ß and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53ß and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Δ133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Δ133p53 isoform, we determined that Δ133p53α and Δ133p53γ but not Δ133p53ß, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Δ133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of Δ133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Δ133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.


Asunto(s)
Neoplasias Encefálicas/irrigación sanguínea , Glioblastoma/irrigación sanguínea , Neovascularización Patológica/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/metabolismo , Animales , Neoplasias Encefálicas/patología , Bovinos , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/metabolismo , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Carga Tumoral , Proteína p53 Supresora de Tumor/metabolismo
10.
Br J Cancer ; 93(8): 855-8, 2005 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-16189517

RESUMEN

Angiogenesis research investigates the formation of new blood vessels in wound healing, tumour growth and embryonic development. Circulating, bone marrow-derived endothelial progenitor cells (EPCs) were first described 8 years ago, yet the exact nature of these endothelial precursor cells remains unclear. The contributions of circulating EPCs to angiogenesis in tumours, ischaemic injury and other diseases as well as their usefulness in the repair of wounded hearts and limbs remain under intense investigation.


Asunto(s)
Células Endoteliales/fisiología , Neovascularización Patológica/fisiopatología , Células Madre/fisiología , Médula Ósea/fisiología , Humanos , Neovascularización Fisiológica , Cicatrización de Heridas
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