RESUMO
Hyperphosphatemia is associated with increased cardiovascular risk in patients with renal disease and in healthy individuals. Here we tested whether high phosphate has a role in the pathophysiology of cardiovascular events by interfering with endothelial function, thereby impairing microvascular function and angiogenesis. Protein expression analysis found downregulation of annexin II in human coronary artery endothelial cells, an effect associated with exacerbated shedding of annexin II-positive microparticles by the cells exposed to high phosphate media. EAhy926 endothelial cells exposed to sera from hyperphosphatemic patients also display decreased annexin II, suggesting a negative correlation between serum phosphate and annexin II expression. By using endothelial cell-based assays in vitro and the chicken chorioallantoic membrane assay in vivo, we found that angiogenesis, vessel wall morphology, endothelial cell migration, capillary tube formation, and endothelial survival were impaired in a hyperphosphatemic milieu. Blockade of membrane-bound extracellular annexin II with a specific antibody mimicked the effects of high phosphate. In addition, high phosphate stiffened endothelial cells in vitro and in rats in vivo. Thus, our results link phosphate and adverse clinical outcomes involving the endothelium in both healthy individuals and patients with renal disease.
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Anexina A2/antagonistas & inibidores , Hiperfosfatemia/fisiopatologia , Animais , Anexina A2/análise , Anexina A2/fisiologia , Apoptose , Movimento Celular , Células Cultivadas , Embrião de Galinha , Regulação para Baixo , Humanos , Masculino , Neovascularização Fisiológica , Proteômica , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Rigidez VascularRESUMO
BACKGROUND/AIMS: Recent retrospective studies suggest an association of therapy with erythropoiesis-stimulating agents (ESAs) and increased mortality in renal transplant recipients (RTR). Large artery structure and function are significantly impaired in RTR which contributes to their high cardiovascular morbidity and could be altered by erythropoietin. We aimed to examine the influence of ESA therapy on large artery stiffness and endothelial function in RTR. METHODS: 63 RTR with chronic allograft dysfunction and renal anemia were randomized to a group receiving darbepoetin alfa (Dar) and a control group (Co). At baseline and after 8 months of treatment (cumulative Dar dose 11.1 µg/kg b.w.) brachial and common carotid artery distensibility coefficients, aortic pulse wave velocity, brachial artery flow-mediated and nitroglycerin-mediated vasodilation were measured as well as the following biomarkers of vascular function: vWF, sVCAM, sICAM, E-selectin, t-PA and PAI-1. RESULTS: 23 patients in the Dar group and 17 patients in the Co group were available for per-protocol analysis. Hemoglobin increased significantly from 10.9 to 12.6 g/dl after 8 months in the Dar group, whereas it remained stable at 11.3 g/dl in the Co group. Effects on large artery stiffness, endothelial function and biomarkers of vascular function did not differ significantly between the two groups. CONCLUSION: Therapy with Dar during 8 months did not significantly impact parameters of large artery stiffness and endothelial function in RTR. These data suggest that therapy with erythropoietin does not deteriorate arterial stiffness and endothelial function in RTR.
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Endotélio Vascular/efeitos dos fármacos , Eritropoetina/análogos & derivados , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Disfunção Primária do Enxerto/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos , Anemia/tratamento farmacológico , Anemia/mortalidade , Artéria Braquial/fisiologia , Darbepoetina alfa , Eritropoetina/administração & dosagem , Feminino , Hematínicos/administração & dosagem , Humanos , Falência Renal Crônica/mortalidade , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/mortalidade , Fatores de Risco , Transplante Homólogo , Resultado do Tratamento , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
BACKGROUND: Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors. METHODS: We enrolled 20 norepinephrine-dependent (NE > 0.4 µg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls. RESULTS: SDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8-18.6) vs. septic patients before TPE: 105.8 (30.8-143.4) µg/ml, p < 0.001; vs. after TPE: 70.7 (36.9-109.5) µg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2-21.2) vs. septic patients at inclusion: 2.9 (2.1-5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2-31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE. CONCLUSIONS: Septic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020.
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Arterial hypertension is a major cause of disease-related morbidity and mortality worldwide. It is nearly absent in populations that consume natural foods low in sodium. However, in industrial countries, where the individual intake of sodium is at least 10 times higher, the prevalence of hypertension is approximately 40%. Major population-based studies link a high-sodium and low-potassium diet to an increase in blood pressure. A hallmark of arterial hypertension is endothelial dysfunction characterized by decreased synthesis of nitric oxide (NO). Plasma sodium and potassium are major determinants for the mechanical stiffness of endothelial cells. High plasma sodium levels stiffen endothelial cells and block NO synthesis. Aldosterone is a prerequisite for this action. However, high plasma potassium levels soften endothelial cells and activate NO release. There is increasing evidence that sodium can be stored transiently in considerable amounts and osmotically inactive in the interstitium. Taken together, it is recommended to maintain plasma sodium levels in the low physiologic range and potassium levels in the high physiologic range while suppressing plasma aldosterone as much as possible. A restriction in sodium intake that is accompanied by increased intake of potassium can profoundly improve the prevalence of hypertension and cardiovascular disease.
Assuntos
Aldosterona/fisiologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Potássio/fisiologia , Sódio/fisiologia , Elasticidade/fisiologia , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/prevenção & controle , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Potássio na Dieta , Sódio na Dieta , Resistência Vascular/fisiologiaRESUMO
Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age- and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD.
Assuntos
Endotélio Vascular/fisiopatologia , Nefropatias/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Adulto , Idoso , Apoptose , Doença Crônica , Células Endoteliais/fisiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/química , Óxido Nítrico/biossíntese , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: Induction of heat shock proteins (HSP), i.e. of the major family member HSP70, is an important cytoprotective-resistance mechanism for monocytes/ macrophages (Mphi). Patients on haemodialysis present with a high infectious morbidity and enhanced carcinoma incidence. Renal insufficiency-related alteration of microbicidal and tumoricidal functions of Mphi, major effectors of the immune system, might promote these diseases. METHODS: Freshly isolated Mphi from Sprague-Dawley rats 2 weeks after 5/6-nephrectomy and from patients on intermittent haemodialysis (IHD) were stimulated by heat shock (HS) and compared to stimulated Mphi of control rats or healthy volunteers (CTR). Expression of HSP72 (inducible HSP70) was assessed by RT-PCR, and/or flow cytometry. Apoptosis of Mphi was detected by flow cytometry (CD14/annexin V-labelling). RESULTS: In rat Mphi, baseline HSP72 expression was similar in both groups, but its induction was significantly impaired in renal insufficiency (214 +/- 68% less HSP70-mRNA versus CTR, n = 6). In patients, HSF-1-mRNA and HSP72-mRNA/protein response to HS was significantly lower, but not affected by dialysis session itself. In parallel, apoptosis of Mphi of patients was enhanced (+83 +/- 29% constitutive apoptotic Mphi versus CTR, n = 8), and HS-dependent protection from apoptosis with and without serum depletion (48 h depletion: HS, +275 +/- 37% apoptotic Mphi versus CTR, n = 6; full medium: +166 +/- 62% versus CTR, n = 8, P < 0.05) was inferior. CONCLUSIONS: Impaired HSP72 stress response of Mphi in patients on haemodialysis might contribute to the observed immune dysfunction and, therefore, to the increased susceptibility to infection and malignancy. Stress impairment is not restricted to uraemia but is already present in a rat model of chronic kidney disease.
Assuntos
Proteínas de Choque Térmico HSP72/biossíntese , Monócitos/metabolismo , Diálise Renal/efeitos adversos , Adolescente , Adulto , Idoso , Animais , Apoptose , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Proteínas de Choque Térmico HSP72/genética , Fatores de Transcrição de Choque Térmico , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/imunologia , Resposta ao Choque Térmico/fisiologia , Humanos , Técnicas In Vitro , Falência Renal Crônica/genética , Falência Renal Crônica/imunologia , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Ureia/farmacologia , Adulto JovemRESUMO
Sodium chloride is a normal and necessary constituent of food and the main cause for the rise in arterial pressure that occurs with age. Changes in dietary salt intake can cause changes in plasma sodium. Even a small increase has been shown to be harmful, for example, by increasing left ventricular mass, thickening and narrowing resistance arteries, and stiffening endothelial cells. Therefore, it is possible that an increase in plasma sodium is an important pressor mechanism. This review discusses the role of dietary sodium and plasma sodium, with a special focus on their impact on the endothelial cell.
Assuntos
Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/efeitos adversos , Sódio/sangue , Tamanho Celular , Dieta Hipossódica , Células Endoteliais , Humanos , Hipertensão/dietoterapia , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico/fisiologia , Sistema Renina-Angiotensina/fisiologia , Resistência Vascular/fisiologia , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Whether the use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker inhibitor (ACEI/ARB) is beneficial in renal transplant recipients remains controversial. In this retrospective study on 505 renal transplant recipients, we analyzed blood pressure and graft survival according to antihypertensive treatment with ACE-I/ARB and/or calcium channel blockers (CCB) over a period of 10 years. Patients were stratified according to their blood pressure 1 year after transplantation [controlled (
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Transplante de Rim , Complicações Pós-Operatórias/tratamento farmacológico , Adolescente , Adulto , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Seguimentos , Rejeição de Enxerto , Humanos , Hipertensão/prevenção & controle , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Reoperação , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: In addition to mandatory CE marking ("CE" representing Conformité Européenne, with the CE marking being a symbol of free marketability in the European Economic Area) for medical devices, there are various seals, initiatives, action groups, etc, in the health app context. However, whether manufacturers use them to distinguish their apps and attach relevance to them is unclear. OBJECTIVE: The objective was to take a snapshot of quality seals, regulatory marks, and other orientation aids available on the German app market and to determine whether manufacturers deem such labels relevant enough to apply them to their apps, namely as reflected by mentions in app description texts in a typical app store (ie, Apple's App Store). METHODS: A full survey of the metadata of 103,046 apps from Apple's German App Store in the Medicine and Health & Fitness categories was carried out. For apps with German-language store descriptions (N=8767), these were automatically searched for the occurrence of relevant keywords and validated manually (N=41). In addition, the websites of various app seal providers were checked for assigned seals. RESULTS: Few manufacturers referenced seals in the descriptions (5/41), although this would have been expected more often based on the seals we were able to identify from the seal providers' Web pages, and there were 34 of 41 that mentioned CE status in the descriptions. Two apps referenced an app directory curated by experts; however, this is not an alternative to CE marks and seals of approval. CONCLUSIONS: Currently, quality seals seem to be irrelevant for manufacturers. In line with regulatory requirements, mentions of medical device status are more frequent; however, neither characteristic is effective for identifying high-quality apps. To improve this situation, a possibly legally obligatory, standardized reporting system should be implemented.
RESUMO
BACKGROUND: Aldosterone at high concentrations causes an expansion of apical surface area and volume of cultured endothelial cells. These morphological changes are associated with endothelial cell stiffening. Here, we tested the hypothesis that the aforementioned aldosterone actions are confined to aldosterone concentrations within the pathophysiological range. Moreover, we investigated whether endothelial cells of venous and arterial origin respond similarly to aldosterone and whether the new aldosterone antagonist eplerenone effectively prevents endothelial cell growth and stiffening. METHODS: We used an endothelial cell line of venous origin (EAHy 926) and primary cultures of human coronary artery endothelial cells (HCAEC). Cells were incubated for 72 h with aldosterone at concentrations of 0.1, 1, 10 and 100 nmol/l. Eplerenone was added at a concentration of 2 micromol/l. Applying atomic force microscopy, we scanned cell layers under fixed and living conditions, allowing measurement of endothelial cell apical surface, volume and cellular stiffness. RESULTS: Aldosterone had comparable effects on EAHy 926 and HCAEC. In EAHy 926, the apical surface increased dose dependently by up to 72 +/- 5% and cell volume by up to 36 +/- 5%. In HCAEC, the maximum increase of apical surface was 78 +/- 6% and maximum cell volume expansion was 58 +/- 6%. Furthermore, aldosterone increased endothelial cell stiffness from 1.47 +/- 0.08 kPa up to 3.95 +/- 0.15 kPa in EAHy 926, and from 1.64 +/- 0.13 kPa up to 4.31 +/- 0.13 kPa in HCAEC. Physiological aldosterone concentrations had no effect, but starting at 1 nmol/l, corresponding to the low pathophysiological range, substantial cell alterations emerged. Eplerenone, at a therapeutic concentration, prevented the observed actions of aldosterone. CONCLUSIONS: Aldosterone-induced endothelial cell growth and stiffening in vitro begins with concentrations in the low pathophysiological range. The preventive action of eplerenone indicates that the endothelium could be a major target of this drug in vivo.
Assuntos
Aldosterona/fisiologia , Crescimento Celular/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiologia , Células Endoteliais/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Vasos Coronários/citologia , Relação Dose-Resposta a Droga , Elasticidade/efeitos dos fármacos , Células Endoteliais/fisiologia , Eplerenona , Humanos , Técnicas In Vitro , Microscopia de Força Atômica , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Espironolactona/análogos & derivados , Espironolactona/farmacologiaRESUMO
The growing number and variety of available mobile health apps makes it increasingly difficult for users to identify apps that match their needs and are safe and trustworthy. Based on the results of a non-systematic search process (internet, PubMed) using terms related to quality and health apps, the presented work aims at giving a short overview over and categorizing existing approaches for assessing and rating the quality of apps to be used in health related contexts.
Assuntos
Aplicativos Móveis/normas , Qualidade da Assistência à Saúde/normas , Telemedicina/normas , HumanosAssuntos
Inflamação/fisiopatologia , Sistema Nervoso Simpático/fisiologia , Anti-Hipertensivos/farmacologia , Atenolol/uso terapêutico , Proteína C-Reativa/metabolismo , Feminino , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Pessoa de Meia-Idade , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismoAssuntos
Transtorno Depressivo Maior/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sistema Nervoso Simpático/efeitos dos fármacosAssuntos
Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Adulto , Seguimentos , Humanos , Transplante de Rim/imunologia , MasculinoRESUMO
BACKGROUND: A 49-year-old woman presented to hospital with an 18-month history of hyponatremic episodes, nausea, vomiting, anorexia and fatigue. INVESTIGATIONS: Physical examination, laboratory tests including full blood count, measurement of electrolytes, hormones, autoantibodies, thyroid and renal function, corticotropin-releasing-hormone stimulation test, 24 h urinalysis and abdominal ultrasonography. DIAGNOSIS: Severe symptomatic hyponatremia in a patient with secondary adrenal insufficiency caused by treatment of lumbago with triamcinolone injections. MANAGEMENT: Hydrocortisone replacement therapy (15 mg daily) for 3 months, followed by a tapering schedule over 12-24 months.
Assuntos
Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/complicações , Hiponatremia/etiologia , Convulsões/etiologia , Triancinolona/efeitos adversos , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Acute renal failure (ARF) due to bilateral parenchymal infiltration of a high grade malignant non-Hodgkin B-cell lymphoma is exceptional. Early identification of this pathology causing ARF is critical as early induction therapy with cyclophosphamide and prednisone often leads to a substantial recovery of kidney function. This striking case illustrates the usefulness of noninvasive fluoro-deoxy-glucose positron emission tomography/computed tomography as a functional imaging modality demonstrating not only the cause of unexplained ARF but also its convenience for the restaging management of non-Hodgkin lymphomas during complete remission.
Assuntos
Injúria Renal Aguda/diagnóstico por imagem , Injúria Renal Aguda/etiologia , Fluordesoxiglucose F18 , Linfoma de Células B/complicações , Linfoma de Células B/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Injúria Renal Aguda/patologia , Biópsia , Feminino , Seguimentos , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Linfoma de Células B/patologia , Pessoa de Meia-Idade , Imagem Corporal TotalRESUMO
BACKGROUND: Nebivolol (NEB) is a [beta]1-receptor blocker with nitric oxide-dependent vasodilating properties. NEB-induced nitric oxide release is mediated through the estrogen receptor. METHOD: Here, we tested the hypothesis that NEB decreases endothelial cell stiffness and that these effects can be abolished by both endothelial nitric oxide synthase and estrogen receptor blockade. Human endothelial cells (EAHy-926) were incubated with vehicle, NEB 0.7 nmol/l, metoprolol 200 nmol/l, 17[beta]-estradiol (E2) 15 nmol/l, the estrogen receptor antagonists tamoxifen 100 nmol/l and ICI 182780 (ICI) 100 nmol/l, the nitric oxide synthase inhibitor N[omega]-nitro-L-arginine methyl ester 1 mmol/l and combinations of NEB and E2 with either tamoxifen, ICI or N[omega]-nitro-L-arginine methyl ester as well as metoprolol and ICI. Atomic force microscopy was performed to measure cellular stiffness, cell volume and apical surface. Presence of estrogen receptor protein in EAHy-926 was confirmed by western blot analysis; quantification of ER[alpha] and ER[beta] total RNA was performed by semiquantitative PCR. RESULTS: Both NEB as well as E2 decreased cellular stiffness to a similar extent (NEB: 0.83 +/- 0.03 pN/nm, E2: 0.87 +/- 0.03 pN/nm, vehicle: 2.19 +/- 0.07 pN/nm), whereas metoprolol had no effect on endothelial stiffness (2.07 +/- 0.04 pN/nm, all n = 60, P < 0.01). The decrease in stiffness occurred as soon as 5 min after starting NEB incubation. The effects are mediated through nongenomic ER[beta] pathways, as ER[alpha] is not translated into measurable protein levels in EAHy-926. Furthermore, NEB increased cell volume by 48 +/- 4% and apical surface by 34 +/- 3%. E2 had comparable effects. Tamoxifen, ICI and N[omega]-nitro-L-arginine methyl ester substantially diminished the effects of NEB and E2. CONCLUSION: NEB decreases cellular stiffness and causes endothelial cell growth. These effects are nitric oxide-dependent and mediated through nongenomic ER[beta] pathways. The morphological and functional alterations observed in endothelial cells may explain improved endothelial function with NEB treatment.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Benzopiranos/farmacologia , Células Endoteliais/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Etanolaminas/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Arginina/análogos & derivados , Arginina/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Tamanho Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Elasticidade/efeitos dos fármacos , Células Endoteliais/ultraestrutura , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor beta de Estrogênio/antagonistas & inibidores , Estrogênios/farmacologia , Feminino , Fulvestranto , Genes Reporter , Humanos , Metoprolol/farmacologia , Nanotecnologia/métodos , Nebivolol , Óxido Nítrico/metabolismo , Nitritos/análise , Tamoxifeno/farmacologia , Fatores de Tempo , TransfecçãoRESUMO
Vascular actions of steroid hormones have gained increasing importance. Indeed, some steroid hormones favorably influence vascular structure and function, whereas others are detrimental. This review will focus on the endothelial effects of steroid hormones. In the first part, we summarize data from in vivo studies elucidating the regulation of endothelial function by steroid hormones. Accumulating data argue for an improvement of endothelium-derived relaxation and impaired vascular contraction by estradiol, whereas testosterone, progesterone, and aldosterone have contrary effects. In the second part, we present data from novel atomic force microscopy studies performed in living endothelial cells under the influence of steroid hormones. These studies provide insight into structural and functional alterations of endothelial cells characterized by changes in volume, apical surface, and stiffness. We summarize the available evidence that changes in shape of endothelial cells translate into changes of endothelial cell stiffness. Under the influence of estradiol, endothelial cells become spherical with consecutive improvement of elasticity, whereas aldosterone flattens endothelial cell-shape leading to increased stiffness. Both, endothelial cell shape and stiffness are major determinants of endothelial nitric oxide production. These studies emphasize the great potential of atomic force microscopy to investigate the function of living endothelial cells.
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Endotélio Vascular/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Microscopia de Força Atômica , Animais , Forma Celular/fisiologia , Elasticidade , Endotélio Vascular/citologia , Endotélio Vascular/ultraestrutura , Humanos , Óxido Nítrico/fisiologiaRESUMO
There is growing evidence that aldosterone acts on heart where it causes cellular remodeling and hypertrophy. Since it is still unclear whether aldosterone directly acts on cardiomyocytes or indirectly, by an altered electrolyte balance in the organism, we applied atomic force microscopy (AFM) in primary cultures of neonatal mouse cardiomyocytes to measure hormone-induced changes in cell volume and plasma membrane surface. AFM measures cell volume and, at the same time, provides quantitative information on cell surface properties. Neonatal mouse cardiomyocytes were cultured for 28 hours in absence or presence of 100 nM aldosterone. Spironolactone was applied as a selective aldosterone receptor antagonist. At the microscopic level, single cell volume and single cell surface were found unchanged by aldosterone. However, nanoscopy of the cell surface, i.e. analysis of the plasma membrane at the nanometer level, revealed a specific increase in plasma membrane nano-enfoldings (roughness). This aldosterone-mediated increase in cell surface roughness was completely prevented by spironolactone. We conclude: (i) Aldosterone directly acts upon cardiomyocytes. (ii) At the microscopic level, no changes of cell volume and cell surface are detectable. (iii) At the nanoscopic level, aldosterone increases plasma membrane roughness. These nanometer changes, detectable only with AFM in cells scanned in fluid after fixation under physiological conditions, indicate plasma membrane remodeling of cardiomyocytes by mineralocorticoids.