RESUMEN
Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia , Mitocondrias , Oxígeno , Vasodilatación , Animales , Mitocondrias/metabolismo , Oxígeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Transducción de Señal , Masculino , Hipoxia/metabolismo , Ratones Endogámicos C57BL , Arterias/metabolismo , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/genética , Ratones Noqueados , Transporte de Electrón , Canales de Calcio/metabolismo , Canales de Calcio/genéticaRESUMEN
Torilis japonica (TJ) fruit, is a herb that is traditionally used for erectile dysfunction (ED). Given the shared mechanisms of ED and hypertension through vascular smooth muscle, we hypothesized that TJ would be effective in vasodilation and blood pressure reduction. This study confirmed the authenticity of TJ samples via DNA barcoding and quantified the main active compound, torilin, using HPLC. TJ was extracted with distilled water (TJW) and 50% ethanol (TJE), yielding torilin contents of 0.35 ± 0.01% and 2.84 ± 0.02%, respectively. Ex vivo tests on thoracic aortic rings from Sprague-Dawley rats showed that TJE (3-300 µg/mL) induced endothelium-independent, concentration-dependent vasodilation, unlike TJW. Torilin caused concentration-dependent relaxation with an EC50 of 210 ± 1.07 µM. TJE's effects were blocked by a voltage-dependent K+ channel blocker and alleviated contractions induced by CaCl2 and angiotensin II. TJE inhibited vascular contraction induced by phenylephrine or KCl via extracellular CaCl2 and enhanced inhibition with nifedipine, indicating involvement of voltage-dependent and receptor-operated Ca2+ channels. Oral administration of TJE (1000 mg/kg) significantly reduced blood pressure in spontaneously hypertensive rats. These findings suggest TJ extract's potential for hypertension treatment through vasorelaxant mechanisms, though further research is needed to confirm its efficacy and safety.
Asunto(s)
Presión Sanguínea , Endotelio Vascular , Frutas , Extractos Vegetales , Ratas Sprague-Dawley , Vasodilatación , Animales , Ratas , Vasodilatación/efectos de los fármacos , Extractos Vegetales/farmacología , Presión Sanguínea/efectos de los fármacos , Masculino , Frutas/química , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Antihipertensivos/farmacología , Vasodilatadores/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Ratas Endogámicas SHR , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatologíaRESUMEN
BACKGROUND: In assessing the effects of smoking cessation on endothelial function, low-flow-mediated constriction (L-FMC) may provide complementary information to flow-mediated dilation (FMD). However, the value of flow-mediated total dilation (FMTD), an index that incorporates L-FMC into FMD, remains underreported. We aimed to evaluate the effect of smoking cessation on endothelial function, as assessed by FMD and FMTD, and clarify its associated clinical factors. METHODS: We enrolled 118 consecutive current smokers without previous coronary artery disease (72.9% were men; age: 59 ± 11 years) who underwent smoking cessation treatment. The clinical variables %FMD, %L-FMC, and %FMTD were examined before and 20 weeks after treatment initiation. A multivariate linear regression model was used to investigate the effects of smoking cessation on %FMD and %FMTD and the interaction between smoking cessation and baseline clinical variables. RESULTS: After 20 weeks, 85 smokers (69.4% were men; age: 59 ± 12 years) ceased smoking (abstainers), whereas 33 smokers (81.8% were men; age: 58 ± 11 years) did not (continued smokers). The estimated group differences (abstainers - continued smokers) in changes in the %FMD and %FMTD were 0.77% (95% confidence interval [CI], -0.22-1.77%; p = 0.129) and 1.17% (95% CI, 0.16-2.18%; p = 0.024), respectively. Smoking cessation-associated improvement in %FMTD was greater in women than in men (5.41% [95% CI, 3.15-7.67%] versus 0.24% [95% CI, -0.81-1.28%]; p-value for interaction, < 0.001). Additionally, a greater %FMTD improvement was observed in patients who smoked fewer cigarettes per day (p-value for interaction, 0.042) and those who had a smaller resting baseline lumen diameter (Dbase) (p-value for interaction, 0.023). CONCLUSIONS: Smoking cessation was associated with an improvement in %FMTD. Sex, cigarettes smoked per day, and Dbase significantly affected this improvement. The FMTD may help in risk stratification after smoking cessation.
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Endotelio Vascular , Cese del Hábito de Fumar , Vasodilatación , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cese del Hábito de Fumar/métodos , Endotelio Vascular/fisiopatología , Vasodilatación/fisiología , Arteria Braquial/fisiopatología , Fumar/fisiopatología , Fumar/efectos adversos , Velocidad del Flujo Sanguíneo/fisiología , Ultrasonografía , Estudios de SeguimientoRESUMEN
INTRODUCTION: The exposome concept includes nutrition as it significantly influences human health, impacting the onset and progression of diseases. Gluten-containing wheat products are an essential source of energy for the world's population. However, a rising number of non-celiac healthy individuals tend to reduce or completely avoid gluten-containing cereals for health reasons. AIM AND METHODS: This prospective interventional human study aimed to investigate whether short-term gluten avoidance improves cardiovascular endpoints and quality of life (QoL) in healthy volunteers. A cohort of 27 participants followed a strict gluten-free diet (GFD) for four weeks. Endothelial function measured by flow-mediated vasodilation (FMD), blood testing, plasma proteomics (Olink®) and QoL as measured by the World Health Organisation Quality-of-Life (WHOQOL) survey were investigated. RESULTS: GFD resulted in decreased leucocyte count and C-reactive protein levels along with a trend of reduced inflammation biomarkers determined by plasma proteomics. A positive trend indicated improvement in FMD, whereas other cardiovascular endpoints remained unchanged. In addition, no improvement in QoL was observed. CONCLUSION: In healthy individuals, a short-term GFD demonstrated anti-inflammatory effects but did not result in overall cardiovascular improvement or enhanced quality of life.
Asunto(s)
Biomarcadores , Dieta Sin Gluten , Calidad de Vida , Humanos , Masculino , Estudios Prospectivos , Femenino , Biomarcadores/sangre , Adulto , Persona de Mediana Edad , Enfermedades Cardiovasculares/prevención & control , Voluntarios Sanos , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Vasodilatación , Adulto JovenRESUMEN
BACKGROUND: This study aims to analyze the efficacy of metformin on carotid intima media thickness (CIMT) and flow-mediated dilation (FMD) for patients with polycystic ovary syndrome (PCOS). METHODS: A literature search of PubMed, Embase, and the Cochrane Library from inception to December 2023 was conducted. Then, after studies selection and data extraction, the mean difference (MD) with a 95% confidence interval (CI) was used to evaluate metformin efficacy in CIMT and FMD for PCOS patients. Heterogeneity was investigated through subgroup and sensitivity analysis. The protocol of our study has been registered in PROSPERO (CRD42024497239). RESULTS: A total of 12 studies with 248 patients were included. CIMT was lower in the endpoint group (after metformin) compared with the baseline group (before metformin) (MD = -0.11, 95% CI = -0.21 to -0.01, p = 0.04). FMD was higher in the endpoint group compared with the baseline group (MD = 3.25, 95% CI = 1.85 to 4.66, p < 0.01). No statistically significant difference was observed in nitroglycerin-mediated dilation (NMD) between the two groups (MD = 0.65, p = 0.51). Subgroup analysis showed that a relatively lower MD of CIMT in PCOS patients from Europe in the endpoint group compared with the baseline group (MD = -0.09, 95% CI = -0.14 to -0.04, p < 0.001). However, the MD in CIMT was not significantly different between the endpoint group and baseline group in PCOS patients from Asia (p = 0.270). CONCLUSION: Metformin may have a beneficial effect on CIMT and FMD, but not on NMD, suggesting that metformin may help reduce cardiovascular events in PCOS patients. Notably, the clinical efficacy of metformin can be influenced by regional differences and study types.
Asunto(s)
Grosor Intima-Media Carotídeo , Metformina , Síndrome del Ovario Poliquístico , Humanos , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/complicaciones , Metformina/uso terapéutico , Femenino , Vasodilatación/efectos de los fármacos , Hipoglucemiantes/uso terapéuticoRESUMEN
Previous studies have revealed the medicinal and therapeutic effects of Galla chinensis. However, no studies have focused on the antihypertensive effects of G. chinensis. Therefore, we aimed to determine the vasorelaxant and hypotensive effects of G. chinensis 50% ethanolic extract (GCE). To evaluate the vascular relaxing effect of GCE, experiments were conducted using aortic segments dissected from Sprague Dawley rats. GCE showed a vasorelaxant effect via the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, inhibiting Ca2+ channels, and activating K+ channels. The hypotensive effects of GCE were evaluated in spontaneously hypertensive rats (SHRs). The SHRs were randomly divided into a control group and orally administered GCE group (100 or 300 mg/kg). The systolic and diastolic blood pressure decreased significantly by -19.47 ± 4.58% and -31.14 ± 7.66% in the GCE 100 mg/kg group, and -21.64 ± 2.40% and -31.91 ± 5.75% in the GCE 300 mg/kg group at 4 h after administration. Considering its vasorelaxant and hypotensive effects, our results indicate that GCE may be a valuable solution for the control of hypertension. However, further studies on the long-term administration and toxicity of GCE are required.
Asunto(s)
Antihipertensivos , Presión Sanguínea , Extractos Vegetales , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Vasodilatadores , Animales , Vasodilatadores/farmacología , Ratas , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Masculino , Extractos Vegetales/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Óxido Nítrico/metabolismo , Vasodilatación/efectos de los fármacos , GMP Cíclico/metabolismo , Aorta/efectos de los fármacos , Medicamentos Herbarios Chinos , TaninosRESUMEN
Numerous research projects focused on the management of acute pulmonary hypertension as Coronavirus Disease 2019 (COVID-19) might lead to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options have been the subject of several clinical trials. In this experimental study, we aimed to examine the hemodynamic impact of the inhalation of the SIN-1A formulation (N-nitroso-N-morpholino-amino-acetonitrile, the unstable active metabolite of molsidomine, stabilized by a cyclodextrin derivative) in a porcine model of acute pulmonary hypertension. Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and PVR decreased significantly (changes in PAP: -30.1% iNO, -22.1% SIN-1A-5, -31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.
Asunto(s)
Hipertensión Pulmonar , Molsidomina , Óxido Nítrico , Animales , Administración por Inhalación , Molsidomina/farmacología , Molsidomina/análogos & derivados , Porcinos , Óxido Nítrico/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Donantes de Óxido Nítrico/administración & dosificación , Donantes de Óxido Nítrico/farmacología , Vasodilatación/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacología , Vasodilatadores/uso terapéutico , MasculinoRESUMEN
BACKGROUND: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. METHODS: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. RESULTS: In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. CONCLUSIONS: Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Vasos Coronarios , Arterias Meníngeas , Trastornos Migrañosos , Caracteres Sexuales , Vasodilatación , Humanos , Femenino , Masculino , Persona de Mediana Edad , Péptido Relacionado con Gen de Calcitonina/farmacología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Arterias Meníngeas/efectos de los fármacos , Arterias Meníngeas/fisiología , Vasodilatación/fisiología , Vasodilatación/efectos de los fármacos , Adulto , Vasos Coronarios/efectos de los fármacos , AncianoRESUMEN
Dahl salt-sensitive (SS) rats fed a high-salt diet, but not low-salt, exhibit vascular dysfunction. Several substrains of SS rats exist that differ in their blood pressure phenotypes and salt sensitivity. The goal of this study was to investigate whether the John-Rapp-derived SS rat (SS/Jr), which exhibits spontaneous hypertension on a low-salt diet, presents with hallmarks of vascular dysfunction observed in another experimental model of hypertension independent of dietary salt, the spontaneously hypertensive rat (SHR). Endothelium-intact aortic rings and mesenteric resistance arteries were isolated from low-salt fed adult male SS/Jr rats and SHRs, or their respective controls, for isometric wire myography. Vessels were challenged with cumulative concentrations of various vasoactive substances, in the absence or presence of nitric oxide synthase or cyclooxygenase inhibitors. Despite showing some differences in their responses to various vasoactive substances, both SS/Jr rats and SHRs exhibited key features of vascular dysfunction, including endothelial dysfunction and hyperresponsiveness to vasocontractile agonists. In conclusion, this study provides evidence to support the utility of the SS/Jr rat strain maintained on a low-salt diet as a valid experimental model for vascular dysfunction, a key feature of human hypertension.
Asunto(s)
Hipertensión , Arterias Mesentéricas , Ratas Endogámicas Dahl , Ratas Endogámicas SHR , Cloruro de Sodio Dietético , Animales , Masculino , Hipertensión/fisiopatología , Hipertensión/etiología , Ratas , Cloruro de Sodio Dietético/efectos adversos , Arterias Mesentéricas/fisiopatología , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Endotelio Vascular/fisiopatología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Presión Sanguínea/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Dieta HiposódicaRESUMEN
Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.
Asunto(s)
Modelos Animales de Enfermedad , Hipoxia , Arteria Pulmonar , Apnea Obstructiva del Sueño , Vasoconstricción , Animales , Cobayas , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/metabolismo , Hipoxia/fisiopatología , Hipoxia/metabolismo , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Masculino , Fenilefrina/farmacología , Remodelación Vascular , Cuerpo Carotídeo/fisiopatología , Cuerpo Carotídeo/metabolismo , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismo , VasodilataciónRESUMEN
We have previously reported that, in aortic rings, 18:1 lysophosphatidic acid (LPA) can induce both vasodilation and vasoconstriction depending on the integrity of the endothelium. The predominant molecular species generated in blood serum are poly-unsaturated LPA species, yet the vascular effects of these species are largely unexplored. We aimed to compare the vasoactive effects of seven naturally occurring LPA species in order to elucidate their potential pathophysiological role in vasculopathies. Vascular tone was measured using myography, and thromboxane A2 (TXA2) release was detected by ELISA in C57Bl/6 mouse aortas. The Ca2+-responses to LPA-stimulated primary isolated endothelial cells were measured by Fluo-4 AM imaging. Our results indicate that saturated molecular species of LPA elicit no significant effect on the vascular tone of the aorta. In contrast, all 18 unsaturated carbon-containing (C18) LPAs (18:1, 18:2, 18:3) were effective, with 18:1 LPA being the most potent. However, following inhibition of cyclooxygenase (COX), these LPAs induced similar vasorelaxation, primarily indicating that the vasoconstrictor potency differed among these species. Indeed, C18 LPA evoked a similar Ca2+-signal in endothelial cells, whereas in endothelium-denuded aortas, the constrictor activity increased with the level of unsaturation, correlating with TXA2 release in intact aortas. COX inhibition abolished TXA2 release, and the C18 LPA induced vasoconstriction. In conclusion, polyunsaturated LPA have markedly increased TXA2-releasing and vasoconstrictor capacity, implying potential pathophysiological consequences in vasculopathies.
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Aorta , Lisofosfolípidos , Ratones Endogámicos C57BL , Tromboxano A2 , Vasoconstricción , Animales , Tromboxano A2/metabolismo , Vasoconstricción/efectos de los fármacos , Ratones , Lisofosfolípidos/metabolismo , Lisofosfolípidos/farmacología , Aorta/efectos de los fármacos , Aorta/metabolismo , Masculino , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Calcio/metabolismoRESUMEN
BACKROUND: Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) has been associated with increased cardiovascular risk. The aim of this Randomized Double-blind clinical Trial was to evaluate the effects of coenzyme-Q10 supplementation in patients with MASLD in terms of endothelial, vascular and myocardial function. METHODS: Sixty patients with MASLD were randomized to receive daily 240 mg of coenzyme-Q10 or placebo. At baseline and at 6-months, the a)Perfused boundary region of sublingual vessels using the Sideview Darkfield imaging technique, b)pulse-wave-velocity, c)flow-mediated dilation of the brachial artery, d)left ventricular global longitudinal strain, e)coronary flow reserve of the left anterior descending coronary artery and f)controlled attenuation parameter for the quantification of liver steatosis were evaluated. RESULTS: Six months post-treatment, patients under coenzyme-Q10 showed reduced Perfused boundary region (2.18 ± 0.23vs.2.29 ± 0.18 µm), pulse-wave-velocity (9.5 ± 2vs.10.2 ± 2.3 m/s), controlled attenuation parameter (280.9 ± 33.4vs.304.8 ± 37.4dB/m), and increased flow-mediated dilation (6.1 ± 3.8vs.4.3 ± 2.8%), global longitudinal strain (-19.6 ± 1.6vs.-18.8 ± 1.9%) and coronary flow reserve (3.1 ± 0.4vs.2.8 ± 0.4) compared to baseline (p < 0.05). The placebo group exhibited no improvement during the 6-month follow-up period (p > 0.05). In patients under coenzyme-Q10, the reduction in controlled attenuation parameter score was positively related to the reduction in Perfused boundary region and pulse wave velocity and reversely related to the increase in coronary flow reserve and flow-mediated dilation (p < 0.05 for all relations). CONCLUSIONS: Six-month treatment with high-dose coenzyme-Q10 reduces liver steatosis and improves endothelial, vascular and left ventricle myocardial function in patients with MASLD, demonstrating significant improvements in micro- and macro-vasculature function. TRIAL REGISTRATION: NCT05941910.
Asunto(s)
Endotelio Vascular , Ubiquinona , Función Ventricular Izquierda , Humanos , Método Doble Ciego , Ubiquinona/análogos & derivados , Ubiquinona/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Endotelio Vascular/fisiopatología , Endotelio Vascular/efectos de los fármacos , Factores de Tiempo , Suplementos Dietéticos , Anciano , Vasodilatación/efectos de los fármacos , Adulto , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Circulación Coronaria/efectos de los fármacos , Análisis de la Onda del Pulso , Hígado Graso/fisiopatología , Hígado Graso/tratamiento farmacológico , Hígado Graso/diagnósticoRESUMEN
BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.
Asunto(s)
Modelos Animales de Enfermedad , Inflamasomas , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Proteína con Dominio Pirina 3 de la Familia NLR , Fenantrenos , Transducción de Señal , Quinasa Syk , Vasodilatación , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Quinasa Syk/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Fenantrenos/farmacología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Vasodilatación/efectos de los fármacos , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/fisiopatología , Vasodilatadores/farmacología , Fosforilación , Ratones , Aorta/efectos de los fármacos , Aorta/fisiopatología , Aorta/metabolismo , Aorta/enzimología , Apolipoproteínas ERESUMEN
Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.
Asunto(s)
Acetilcisteína , Epigénesis Genética , Retardo del Crecimiento Fetal , Sulfuro de Hidrógeno , Hipoxia , Animales , Sulfuro de Hidrógeno/metabolismo , Acetilcisteína/farmacología , Embrión de Pollo , Humanos , Femenino , Embarazo , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/fisiopatología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Metilación de ADN , Cistationina gamma-Liasa/genética , Cistationina gamma-Liasa/metabolismo , Vasodilatación/efectos de los fármacos , Placenta/metabolismo , Placenta/irrigación sanguínea , Arterias Umbilicales/metabolismoRESUMEN
Endothelial dysfunction is acknowledged as a marker for subclinical target organ damage (STOD) in hypertension, though its therapeutic potential has not yet been clarified. This study assessed whether early endothelial function improvement (EEFI) reduced STOD in patients with essential hypertension (EH). We conducted a retrospective cohort analysis of 456 EH patients initially free from STOD. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD), with values ≤ 7.1% indicating dysfunction. Patients were initially categorized by endothelial status (dysfunction: n = 180, normal: n = 276), and further divided into improved or unimproved groups based on changes within three months post-enrollment. During a median follow-up of 25 months, 177 patients developed STOD. The incidence of STOD was significantly higher in patients with initial dysfunction compared to those with normal function. Kaplan-Meier analysis indicated that the improved group had a lower cumulative incidence of STOD compared to the unimproved group (p < 0.05). Multivariable Cox regression confirmed EEFI as an independent protective factor against STOD in EH patients (p < 0.05), regardless of their baseline endothelial status, especially in those under 65 years old, non-smokers, and with low-density lipoprotein cholesterol levels ≤ 3.4 mmol/L. In conclusion, EEFI significantly reduces STOD incidence in EH patients, particularly in specific subgroups, emphasizing the need for early intervention in endothelial function to prevent STOD.
Asunto(s)
Endotelio Vascular , Hipertensión , Humanos , Masculino , Femenino , Persona de Mediana Edad , Endotelio Vascular/fisiopatología , Anciano , Estudios Retrospectivos , Hipertensión/fisiopatología , Incidencia , Arteria Braquial/fisiopatología , Hipertensión Esencial/fisiopatología , Factores de Riesgo , VasodilataciónRESUMEN
INTRODUCTION: Coexistence of chronic obstructive pulmonary disease(COPD) and heart failure(HF) is associated with systemic inflammation, myocardial injury, and arterial stiffening, impacting cardiovascular risk and prognosis in patients. Arterial stiffness, reduced nitric oxide synthesis, and altered cardiac autonomic control further link COPD and HF pathophysiology, emphasizing the need for comprehensive cardiovascular assessment. OBJECTIVE: To investigate a cardiovascular profile in patients hospitalized with exacerbation COPD(ECOPD) in coexistence with HF compared with isolated diseases. METHODS: A cross-sectional study including patients diagnosed with ECOPD and decompensated HF, approached between 24 and 48 h after hospital admission. Assessments included: endothelial function by brachial artery flow-mediated vasodilation(FMD); hemodynamic through analysis of pulse wave and arterial stiffness by carotid-femoral pulse wave velocity(cfPWV) and cardiac autonomic modulation(CAM) by heart rate variability(HRV). RESULTS: The mean FMD was 4.45 %, indicating endothelial dysfunction in all patients. Date is present in mean(confidence interval) sequency COPD(n = 12), COPD-HF(n = 21) and HF(n = 21). FMD: 5.47(3.96-6.91); 2.66(0.09-3.48); 4.60(2.30-6.43) p < 0.01. However, COPD-HF had worse FMD. Arterial stiffens (AIx: 29.0(19.0-42.6); 34.6(24.3-43.2); 14.5(8.0-24.0)p < 0.01; cfPWV: (6.5(5.4-7.2); 7.7(7.0-8.5); 6.0(5.0-6.5)); COPD-HF also showed greater activation of the sympathetic nervous system compared to patients with isolated diseases (PNS: 1.32(-2.53 to -0.62); -2.33(-2.60 to -2.12); -1.32(-1.42 to -1.01) p < 0.01; SNS: 3.50(1.40-8.55); 7.11(5.70-8.29); 2.32(1.78-5.01) p < 0.01). In addition, rMSSD, NN50, pNN50, and TINN also indicate worse CAM in the COPD-HF group compared to isolated diseases. CONCLUSION: During hospitalization, the worst impairment in vascular function and cardiac autonomic modulation were found in patients with COPD and HF comorbidity compared to the isolated diseases(HF or COPD).
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Endotelio Vascular , Insuficiencia Cardíaca , Hospitalización , Enfermedad Pulmonar Obstructiva Crónica , Rigidez Vascular , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Estudios Transversales , Masculino , Femenino , Hospitalización/estadística & datos numéricos , Anciano , Rigidez Vascular/fisiología , Persona de Mediana Edad , Endotelio Vascular/fisiopatología , Vasodilatación/fisiología , Comorbilidad , Frecuencia Cardíaca/fisiología , Análisis de la Onda del Pulso , Hemodinámica/fisiología , Arteria Braquial/fisiopatología , Sistema Nervioso Autónomo/fisiopatologíaRESUMEN
The mechanisms underlying endothelial dysfunction in Type 1 and Type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and twenty-six patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV) were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared with patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments, whereas RBCs from patients with T1DM did not affect EDR nor EIDR. The present study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms.
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Arginasa , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Endotelio Vascular , Eritrocitos , Vasodilatación , Humanos , Arginasa/metabolismo , Arginasa/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/sangre , Masculino , Eritrocitos/enzimología , Eritrocitos/metabolismo , Femenino , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 1/sangre , Persona de Mediana Edad , Endotelio Vascular/fisiopatología , Animales , Adulto , Anciano , Aorta/fisiopatología , Inhibidores Enzimáticos/farmacologíaRESUMEN
BACKGROUND: Preeclampsia is a serious condition of pregnancy, complicated by aberrant maternal vascular dysfunction. CNP (C-type natriuretic peptide) contributes to vascular homeostasis, acting through NPR-B (natriuretic peptide receptor-B) and NPR-C (natriuretic peptide receptor-C). CNP mitigates vascular dysfunction of arteries in nonpregnant cohorts; this study investigates whether CNP can dilate maternal arteries in ex vivo preeclampsia models. METHODS: Human omental arteries were dissected from fat biopsies collected during cesarean section. CNP, NPR-B, and NPR-C mRNA expression was assessed in arteries collected from pregnancies complicated by preeclampsia (n=6) and normotensive controls (n=11). Using wire myography, we investigated the effects of CNP on dilation of arteries from normotensive pregnancies. Arteries were preconstricted with either serum from patients with preeclampsia (n=6) or recombinant ET-1 (endothelin-1; vasoconstrictor elevated in preeclampsia; n=6) to model vasoconstriction associated with preeclampsia. Preconstricted arteries were treated with recombinant CNP (0.001-100 µmol/L) or vehicle and vascular relaxation assessed. In further studies, arteries were preincubated with NPR-B (5 µmol/L) and NPR-C (10 µmol/L) antagonists before serum-induced constriction (n=4-5) to explore mechanistic signaling. RESULTS: CNP, NPR-B, and NPR-C mRNAs were not differentially expressed in omental arteries from preeclamptic pregnancies. CNP potently stimulated maternal artery vasorelaxation in our model of preeclampsia (using preeclamptic serum). Its vasodilatory actions were driven through the activation of NPR-B predominantly; antagonism of this receptor alone dampened CNP vasorelaxation. Interestingly, CNP did not reduce ET-1-driven omental artery constriction. CONCLUSIONS: Collectively, these data suggest that enhancing CNP signaling through NPR-B offers a potential therapeutic strategy to reduce systemic vascular constriction in preeclampsia.
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Péptido Natriurético Tipo-C , Preeclampsia , Receptores del Factor Natriurético Atrial , Vasodilatación , Femenino , Preeclampsia/fisiopatología , Preeclampsia/metabolismo , Preeclampsia/tratamiento farmacológico , Humanos , Embarazo , Péptido Natriurético Tipo-C/farmacología , Adulto , Receptores del Factor Natriurético Atrial/genética , Receptores del Factor Natriurético Atrial/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Epiplón/irrigación sanguínea , Vasoconstricción/efectos de los fármacos , Arterias/efectos de los fármacos , Arterias/metabolismo , Arterias/fisiopatologíaRESUMEN
In this study, a physics-based model is developed to describe the entire flow mediated dilation (FMD) response. A parameter quantifying the arterial wall's tendency to recover arises from the model, thereby providing a more elaborate description of the artery's physical state, in concert with other parameters characterizing mechanotransduction and structural aspects of the arterial wall. The arterial diameter's behavior throughout the full response is successfully reproduced by the model. Experimental FMD response data were obtained from healthy volunteers. The model's parameters are then adjusted to yield the closest match to the observed experimental response, hence delivering the parameter values pertaining to each subject. This study establishes a foundation based on which future potential clinical applications can be introduced, where endothelial function and general cardiovascular health are inexpensively and noninvasively quantified.
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Arteria Braquial , Modelos Cardiovasculares , Vasodilatación , Humanos , Arteria Braquial/fisiología , Arteria Braquial/diagnóstico por imagen , Vasodilatación/fisiología , Masculino , Adulto , Femenino , Velocidad del Flujo Sanguíneo/fisiologíaRESUMEN
BACKGROUND: Nocturnal hemodialysis (nHD) restores the attenuated brachial artery vasodilator responsiveness of patients receiving conventional intermittent hemodialysis (iHD). Its impact on coronary vasodilatation is unknown. METHODS: We evaluated 25 patients on hemodialysis who fulfilled transplant criteria: 15 on iHD (4-hour sessions, 3 d/wk) and 10 on nHD (≈40 h/wk over 8-10-hour sessions) plus 6 control participants. Following diagnostic angiography, left anterior descending (LAD) coronary flow reserve and mean luminal diameter were quantified at baseline and during sequential intracoronary administration of adenosine (infusion and bolus), nitroglycerin (bolus), acetylcholine (infusion), acetylcholine coinfused with vitamin C, and, finally, sublingual nitroglycerin. RESULTS: Coronary flow reserve in those receiving nHD was augmented relative to iHD (3.28±0.26 versus 2.17±0.12 [mean±SEM]; P<0.03) but attenuated, relative to controls (4.80±0.63; P=0.011). Luminal dilatations induced by intracoronary adenosine and nitroglycerin were similar in nHD and controls but blunted in the iHD cohort (P<0.05 versus both). ACh elicited vasodilatation in controls but constriction in both dialysis groups (both P<0.05, versus control); vitamin C coinfusion had no effect. Sublingual nitroglycerin increased mid-left anterior descending diameter and reduced mean arterial pressure in controls (+15.2±2.68%; -16.00±1.60%) and in nHD recipients (+14.78±5.46%; -15.82±1.32%); iHD responses were markedly attenuated (+1.9±0.86%; -5.89±1.41%; P<0.05, all comparisons). CONCLUSIONS: Coronary and systemic vasodilator responsiveness to both adenosine and nitroglycerin is augmented in patients receiving nHD relative to those receiving iHD, whereas vasoconstrictor responsiveness to acetylcholine does not differ. By improving coronary conduit and microvascular function, nHD may reduce the cardiovascular risk of patients on dialysis.