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1.
Arterioscler Thromb Vasc Biol ; 42(4): 444-461, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35236104

RESUMO

BACKGROUND: TP (thromboxane A2 receptor) plays an eminent role in the pathophysiology of endothelial dysfunction and cardiovascular disease. Moreover, its expression is reported to increase in the intimal layer of blood vessels of cardiovascular high-risk individuals. Yet it is unknown, whether TP upregulation per se has the potential to affect the homeostasis of the vascular endothelium. METHODS: We combined global transcriptome analysis, lipid mediator profiling, functional cell analyses, and in vivo angiogenesis assays to study the effects of endothelial TP overexpression or knockdown/knockout on the angiogenic capacity of endothelial cells in vitro and in vivo. RESULTS: Here we report that endothelial TP expression induces COX-2 (cyclooxygenase-2) in a Gi/o- and Gq/11-dependent manner, thereby promoting its own activation via the auto/paracrine release of TP agonists, such as PGH2 (prostaglandin H2) or prostaglandin F2 but not TxA2 (thromboxane A2). TP overexpression induces endothelial cell tension and aberrant cell morphology, affects focal adhesion dynamics, and inhibits the angiogenic capacity of human endothelial cells in vitro and in vivo, whereas TP knockdown or endothelial-specific TP knockout exerts opposing effects. Consequently, this TP-dependent feedback loop is disrupted by pharmacological TP or COX-2 inhibition and by genetic reconstitution of PGH2-metabolizing prostacyclin synthase even in the absence of functional prostacyclin receptor expression. CONCLUSIONS: Our work uncovers a TP-driven COX-2-dependent feedback loop and important effector mechanisms that directly link TP upregulation to angiostatic TP signaling in endothelial cells. By these previously unrecognized mechanisms, pathological endothelial upregulation of the TP could directly foster endothelial dysfunction, microvascular rarefaction, and systemic hypertension even in the absence of exogenous sources of TP agonists.


Assuntos
Células Endoteliais , Receptores de Tromboxanos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Células Endoteliais/metabolismo , Retroalimentação , Homeostase , Humanos , Receptores de Tromboxanos/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/genética , Tromboxano A2/metabolismo , Tromboxanos/metabolismo , Tromboxanos/farmacologia
2.
Pharmacopsychiatry ; 54(3): 101-105, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33197939

RESUMO

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) has been implicated in the pro-neurogenic effect of selective serotonin reuptake inhibitors. In this study, we used Tph2 -/- mice lacking brain serotonin to dissect the interplay between BDNF and the serotonin system in mediating the effects of antidepressant pharmacotherapy on adult neurogenesis in the hippocampus. METHODS: Besides citalopram (CIT), we tested tianeptine (TIA), an antidepressant whose mechanism of action is not well understood. Specifically, we examined cell survival and endogenous concentrations of BDNF following daily injection of the drugs. RESULTS: Twenty-one days of CIT, but not of TIA, led to a significant increase in the survival of newly generated cells in the dentate gyrus of wild-type mice, without a significant effect on BDNF protein levels by either treatment. In Tph2 -/- mice, adult neurogenesis was consistently increased. Furthermore, Tph2 -/- mice showed increased BDNF protein levels, which were not affected by TIA but were significantly reduced by CIT. DISCUSSION: We conclude that the effects of CIT on adult neurogenesis are not explained by changes in BDNF protein concentrations in the hippocampus.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Citalopram , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citalopram/farmacologia , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Neurogênese
3.
Eur Arch Psychiatry Clin Neurosci ; 268(8): 861-864, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30019210

RESUMO

Compounds targeting serotonin (5-HT) are widely used as antidepressants. However, the role of 5-HT in mediating the effects of electroconvulsive seizure (ECS) therapy remains undefined. Using Tph2-/- mice depleted of brain 5-HT, we studied the effects of ECS on behavior and neurobiology. ECS significantly prolonged the start latency in the elevated O-Maze test, an effect that was abolished in Tph2-/- mice. Furthermore, in the absence of 5-HT, the ECS-induced increase in adult neurogenesis and in brain-derived neurotrophic factor signaling in the hippocampus were significantly reduced. Our results indicate that brain 5-HT critically contributes to the neurobiological responses to ECS.


Assuntos
Encéfalo/metabolismo , Eletroconvulsoterapia/métodos , Convulsões/terapia , Serotonina/metabolismo , Animais , Bromodesoxiuridina/metabolismo , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologia , Convulsões/genética , Estatísticas não Paramétricas , Natação/psicologia , Triptofano Hidroxilase/deficiência , Triptofano Hidroxilase/genética
4.
Biochem Pharmacol ; 219: 115916, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37979705

RESUMO

The thromboxane A2 receptor (TP) has been shown to play a role in angiotensin II (Ang II)-mediated hypertension and pathological vascular remodeling. To assess the impact of vascular TP on Ang II-induced hypertension, atherogenesis, and pathological aortic alterations, i.e. aneurysms, we analysed Western-type diet-fed and Ang II-infused TPVSMC KO/Ldlr KO, TPEC KO/Ldlr KO mice and their respective wild-type littermates (TPWT/Ldlr KO). These analyses showed that neither EC- nor VSMC-specific deletion of the TP significantly affected basal or Ang II-induced blood pressure or aortic atherosclerotic lesion area. In contrast, VSMC-specific TP deletion abolished and EC-specific TP deletion surprisingly reduced the ex vivo reactivity of aortic rings to the TP agonist U-46619, whereas VSMC-specific TP knockout also diminished the ex vivo response of aortic rings to Ang II. Furthermore, despite similar systemic blood pressure, there was a trend towards less atherogenesis in the aortic arch and a trend towards fewer pathological aortic alterations in Ang II-treated female TPVSMC KO/Ldlr KO mice. Survival was impaired in male mice after Ang II infusion and tended to be higher in TPVSMC KO/Ldlr KO mice than in TPWT/Ldlr KO littermates. Thus, our data may suggest a deleterious role of the TP expressed in VSMC in the pathogenesis of Ang II-induced aortic atherosclerosis in female mice, and a surprising role of the endothelial TP in TP-mediated aortic contraction. However, future studies are needed to substantiate and further elucidate the role of the vascular TP in the pathogenesis of Ang II-induced hypertension, aortic atherosclerosis and aneurysm formation.


Assuntos
Aterosclerose , Hipertensão , Receptores de Tromboxanos , Animais , Feminino , Masculino , Camundongos , Angiotensina II/toxicidade , Aorta , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/patologia , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Tromboxanos/genética
5.
Free Radic Biol Med ; 185: 36-45, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35470061

RESUMO

The F2-isoprostane 8-iso-PGF2α (also known as 15-F2t-isoprostane, iPF2α-III, 8-epi PGF2α, 15(S)-8-iso-PGF2α, or 8-Isoprostane), a thromboxane A2 receptor (TP) agonist, stable biomarker of oxidative stress, and risk marker of cardiovascular disease, has been proposed to aggravate atherogenesis in genetic mouse models of atherosclerotic vascular disease. Moreover, the TP plays an eminent role in the pathophysiology of endothelial dysfunction, atherogenesis, and cardiovascular disease. Yet it is unknown, how the TP expressed by vascular cells affects atherogenesis or 8-iso-PGF2α-related effects in mouse models of atherosclerosis. We studied Ldlr-deficient vascular endothelial-specific (EC) and vascular smooth muscle cell (VSMC)-specific TP knockout mice (TPECKO/Ldlr KO; TPVSMCKO/Ldlr KO) and corresponding wild-type littermates (TPWT/Ldlr KO). The mice were fed a Western-type diet for eight weeks and received either 8-iso-PGF2α or vehicle infusions via osmotic pumps. Subsequently, arterial blood pressure, atherosclerotic lesion formation, and lipid profiles were analyzed. We found that VSMC-, but not EC-specific TP deletion, attenuated atherogenesis without affecting blood pressure or plasma lipid profiles of the mice. In contrast to a previous report, 8-iso-PGF2α tended to reduce atherogenesis in TPWT/Ldlr KO and TPEC KO/Ldlr KO mice, again without significantly affecting blood pressure or lipid profiles of these mice. However, no further reduction in atherogenesis was observed in 8-iso-PGF2α-treated TPVSMC KO/Ldlr KO mice. Our work suggests that the TP expressed in VSMC but not the TP expressed in EC is involved in atherosclerotic lesion formation in Ldlr-deficient mice. Furthermore, we report an inhibitory effect of 8-iso-PGF2α on atherogenesis in this experimental atherosclerosis model, which paradoxically appears to be related to the presence of the TP in VSMC.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Animais , Aterosclerose/genética , Dinoprosta/análogos & derivados , F2-Isoprostanos , Camundongos , Camundongos Knockout , Fator de Crescimento Placentário , Receptores de Tromboxanos/genética , Tromboxano A2 , Tromboxanos
6.
Cells ; 10(11)2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34831469

RESUMO

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.


Assuntos
Envelhecimento/fisiologia , Comportamento Animal , Técnicas de Silenciamento de Genes , Neurogênese , Serotonina/metabolismo , Animais , Contagem de Células , Proliferação de Células , Giro Denteado/citologia , Feminino , Fenótipo , Córtex Pré-Frontal/metabolismo , Núcleos da Rafe/metabolismo , Ratos Sprague-Dawley , Triptofano Hidroxilase/metabolismo
7.
Biomed Opt Express ; 9(9): 4130-4148, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30615700

RESUMO

We investigate the origin of high frequency noise in Fourier domain mode locked (FDML) lasers and present an extremely well dispersion compensated setup which virtually eliminates intensity noise and dramatically improves coherence properties. We show optical coherence tomography (OCT) imaging at 3.2 MHz A-scan rate and demonstrate the positive impact of the described improvements on the image quality. Especially in highly scattering samples, at specular reflections and for strong signals at large depth, the noise in optical coherence tomography images is significantly reduced. We also describe a simple model that suggests a passive physical stabilizing mechanism that leads to an automatic compensation of remaining cavity dispersion in FDML lasers.

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