Remodelado vascular excéntrico: su relación con trastornos metabólicos y el incremento de la masa corporal / Eccentric Vascular Remodeling: Its Relationship with Metabolic Disorders and Increased Body Mass

RESUMEN Introducción: Existe evidencia reciente que establecería a la hipoperfusión muscular como causa primaria de trastornos metabólicos en respuesta a la sobrealimentación. Esta concepción centrípeta del desarrollo de trastornos metabólicos podría implicar no solo alteraciones en la microvasculatura, sino también afectación en las arterias de conductancia. Objetivos: 1) Determinar la asociación entre diámetro basal de la arteria humeral (D-Hum) y la vasodilatación mediada por flujo (VDMF) 2) Analizar la asociación de ambos parámetros conforme aumenta de la masa corporal 3) Evaluar asociaciones entre el D-Hum/VDMF con componentes del síndrome metabólico (SM) 4) Evaluar la asociación independiente de ambas variables con el SM. Material y métodos: Se evaluaron 3493 pacientes. Se excluyeron pacientes < 18 y >80 años, con patología cardiovascular previa, insuficiencia renal crónica (IRC), colagenopatías, y tratados con estatinas. Se determinó presión arterial (PA), parámetros antropométricos y perfil metabólico, y se clasificó a los sujetos de acuerdo con la presencia de SM según AHA/NHLBI 2019. Se midieron D-Hum en mm y VDMF en %. Se analizó la asociación lineal entre D-Hum y VDMF y se analizaron ambas variables según decilos de índice de masa corporal (IMC). Se evaluaron asociaciones entre D-Hum/VDMF con la PA, glucemia (Glu), triglicéridos (TG) y colesterol de alta densidad (HDLc). Se realizaron dos regresiones logísticas con SM como variable dependiente y D-Hum o VDMF más edad, sexo, IMC y factores de riesgo coronario (FRC) como independientes. Resultados: Ingresaron 1995 pacientes (48,2 ± 11 años, 56 % hombres). El D-Hum y la VDMF presentaron una asociación inversa (r= -0,42; p < 0,0001). El D-Hum aumentó según decilos del IMC (p < 0,000001); la VDMF mostró relación inversa con los decilos crecientes de IMC (p < 0,000001). El D-Hum presentó correlación directa con PA, Glu y TG; e inversa con HDLc (p < 0,05 en todos los casos). La VDMF mostró correlación inversa con PA, Glu y TG; y directa con HDLc (p < 0,05 en todos los casos). El D-Hum se asoció en forma independiente con el SM ajustado por edad, sexo, IMC y FRC (OR 1,42, p = 0,0019), mientras que la VDMF no (OR 0,98, p = 0,217). Conclusión: El remodelado vascular excéntrico se asoció con un compromiso en la adaptación vascular ante aumentos en la demanda de flujo sanguíneo y con alteraciones metabólicas a lo largo del incremento de la masa corporal. Así, el compromiso dinámico de la vasculatura podría tener un rol determinante en el desarrollo de alteraciones metabólicas en forma sincrónica con la ganancia de peso.

ABSTRACT Background: Recent evidence would establish muscle hypoperfusion as the primary cause of metabolic disorders in response to overfeeding. This centripetal concept on the development of metabolic disorders could involve not only alterations in the microvasculature, but also affect the conductance arteries. Objectives: The aim of this study was 1) to determine the association between baseline brachial artery diameter (BAD) and flow-mediated vasodilation (FMVD), 2) To analyze the association of both parameters throughout the increase in body mass, 3) To evaluate associations between BAD/FMVD with components of the metabolic syndrome (MS) and 4) To evaluate the independent association of both variables with MS. Methods: A total of 3493 patients were evaluated. Patients <18 and >80 years old, those with previous cardiovascular disease, chronic kidney disease (CKD), collagenopathies, or treated with statins were excluded from the study. Blood pressure (BP), anthropometric parameters and metabolic profile were determined, and the subjects were classified according to the presence of MS conforming AHA/NHLBI 2019 criteria. BAD was measured in mm and FMVD as percentage. The linear association between BAD and FMVD was assessed, and both variables were analyzed according to deciles of body mass index (BMI). Associations between BAD/FMVD with BP, glucose (Glu), triglycerides (TG) and high-density cholesterol (HDL-C) levels were evaluated. Two logistic regression analyses were performed with MS as dependent variable and BAD or FMVD plus age, gender, BMI, and coronary risk factors (CRF) as independent variables. Results: A total of 1995 patients (48.2 ± 11 years, 56% men) were admitted in the study. An inverse correlation was found between BAD and FMVD (r= -0.42; p < 0.0001). BAD increased according to deciles of BMI (p < 0.000001), while FMVD showed an inverse relationship with increasing deciles of BMI (p < 0.000001). BAD exhibited a direct correlation with BP, Glu and TG; and an inverse relationship with HDL-C (p < 0.05 in all cases). FMVD presented an inverse correlation with BP, Glu and TG; and a direct correlation with HDL-C (p < 0.05 in all cases). BAD was independently associated with MS adjusted for age, gender, BMI and CRF (OR 1.42, p=0.0019), while FMVD was not (OR 0.98, p = 0.217). Conclusion: Eccentric vascular remodeling was associated with vascular adaptation to increased blood flow demand and with metabolic alterations throughout the increase in body mass. Thus, the dynamic compromise of vasculature could play a decisive role in the development of metabolic alterations occurring synchronously with weight gain.

Effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension in mice and its mechanism / 中国药理学通报

Aim To study the effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension and explore the underlying mechanism in mice. Methods 10 to 12 weeks old wild type (WT) mice and TRPM8 gene knockout (TRPM8

Potassium dehydroandrographolide succinate regulates the MyD88/CDH13 signaling pathway to enhance vascular injury-induced pathological vascular remodeling / 中国天然药物

Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.

Effects of atorvastatin in suppressing pulmonary vascular remodeling in rats with chronic obstructive pulmonary disease

Abstract Objective To investigate the effects of atorvastatin calcium on pulmonary vascular remodeling, the authors explored the regulatory mechanism of Histone Deacetylation Enzyme-2 (HDAC2) in rats with Chronic Obstructive Pulmonary Disease (COPD), and provided a new direction for drug treatment in the progression of vascular remodeling. Methods Eighteen female SD rats were randomly divided into control (Group S1), COPD (Group S2), and atorvastatin calcium + COPD (Group S3) groups. A COPD rat model was established by passive smoking and intratracheal injection of Lipopolysaccharide (LPS). Haematoxylin and eosin staining and Victoria Blue + Van Gibson staining were used to observe pathological changes in the lung tissue. The pulmonary vascular inflammation score was calculated, and the degree of pulmonary vascular remodeling was evaluated. The ratio of Muscular Arteries in lung tissue (MA%), the ratio of the vessel Wall Area to the vessel total area (WA%), and the ratio of the vessel Wall Thickness to the vascular outer diameter (WT%) were measured using imaging software. The expression of HDAC2 was measured using western blotting, ELISA (Enzyme-Linked Immunosorbent Assay), and qPCR (Real-time PCR). Results Compared with the control group, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling increased in rats with COPD. The WT%, WA%, and lung inflammation scores increased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissue decreased, and the level of Vascular Endothelial Growth Factor (VEGF) in the lung tissues increased (p< 0.05). Compared with the COPD group, the lung tissues from rats in the atorvastatin group had fewer inflammatory cells, and the vascular pathological changes were significantly relieved. The WT%, WA%, and lung inflammation scores decreased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissues increased, and the level of VEGF in the lung tissues decreased (p< 0.05). Conclusion The present study revealed that atorvastatin calcium could regulate the contents and expression of HDAC2 in serum and lung tissues and inhibit the production of VEGF, thereby regulating pulmonary vascular remodeling in a rat model with COPD.

Experimental and clinical research progress of traditional Chinese medicine promoting blood circulation and removing blood stasis in treatment of pulmonary hypertension / 中国药理学通报

Pulmonary hypertension(PH)is a type of progressive cardiovascular disease or clinical syndrome. Its pathological mechanism is complex. The existing clinical drugs cannot well inhibit the progression of the disease. Traditional Chinese Medicine(TCM)has unique advantages in the treatment of PH due to its synergistic effect of multiple components and multiple targets. Recent studies have found that the TCM of promoting blood circulation and removing blood stasis can play a significant role in the treatment of PH, such as dilating pulmonary blood vessels, improving endothelial function, and relieving right heart failure. This article briefly summarizes and discusses the therapeutic effect and mechanism of TCM that can promote blood circulation and remove blood stasis in treatment of PH.

Mechanism of high-salt diet up-regulating TMEM16A-induced cerebral arterial remodeling in C57BL/6J mice / 中国药理学通报

Aim To investigate the mechanism of high salt-induced cerebral artery remodeling in mice by up-regulating TMEM16A. Methods Forty C57BL/6J mice were randomly divided into four groups (10 per group, 8 weeks of intervention), namely, blank control group (normal diet), low-salt group (2% high salt diet), medium-salt group (4% high salt diet) and high-salt group (8% high salt diet). HE staining was used to observe the morphological changes of cerebral arteries; blood vessel permeability test was used to compare the color and absorbance value of brain tissue. Immunofluorescence was employed to detect TMEM16A expression in cerebral arteries of mice in each group; PCR and Western blot were applied to detect the mRNA and protein expression of TMEM16A in cerebral arterial tissues; whole-cell patch clamp was use to record the calcium-activated chloride channel (CaCC) currents of mouse cerebral artery smooth muscle cells in each group. Results HE results showed that 2%, 4%, and 8% high salt diet could concentra-tion-dependently induce cerebral arterial wall thickening and lumen stenosis in C57BL/6J mice. The permeability test found that compared with the control group, the absorbance value of the brain tissue of the mice in the 2%, 4% and 8% high salt groups increased significantly. The results of isolated muscle tension showed that compared with the control group, the systolic response of isolated cerebral arteries to 60 mmol • L

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Effect of platelet-derived growth factor-BB on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension and its mechanism / 中国当代儿科杂志

OBJECTIVES@#To study the effect of platelet-derived growth factor-BB (PDGF-BB) on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH).@*METHODS@#A total of 128 neonatal rats were randomly divided into four groups: PDGF-BB+HPH, HPH, PDGF-BB+normal oxygen, and normal oxygen (n=32 each). The rats in the PDGF-BB+HPH and PDGF-BB+normal oxygen groups were given an injection of 13 μL 6×1010 PFU/mL adenovirus with PDGF-BB genevia the caudal vein. After 24 hours of adenovirus transfection, the rats in the HPH and PDGF-BB+HPH groups were used to establish a neonatal rat model of HPH. Right ventricular systolic pressure (RVSP) was measured on days 3, 7, 14, and 21 of hypoxia. Hematoxylin-eosin staining was used to observe pulmonary vascular morphological changes under an optical microscope, and vascular remodeling parameters (MA% and MT%) were also measured. Immunohistochemistry was used to measure the expression levels of PDGF-BB and proliferating cell nuclear antigen (PCNA) in lung tissue.@*RESULTS@#The rats in the PDGF-BB+HPH and HPH groups had a significantly higher RVSP than those of the same age in the normal oxygen group at each time point (P<0.05). The rats in the PDGF-BB+HPH group showed vascular remodeling on day 3 of hypoxia, while those in the HPH showed vascular remodeling on day 7 of hypoxia. On day 3 of hypoxia, the PDGF-BB+HPH group had significantly higher MA% and MT% than the HPH, PDGF-BB+normal oxygen, and normal oxygen groups (P<0.05). On days 7, 14, and 21 of hypoxia, the PDGF-BB+HPH and HPH groups had significantly higher MA% and MT% than the PDGF-BB+normal oxygen and normal oxygen groups (P<0.05). The PDGF-BB+HPH and HPH groups had significantly higher expression levels of PDGF-BB and PCNA than the normal oxygen group at all time points (P<0.05). On days 3, 7, and 14 of hypoxia, the PDGF-BB+HPH group had significantly higher expression levels of PDGF-BB and PCNA than the HPH group (P<0.05), while the PDGF-BB+normal oxygen group had significantly higher expression levels of PDGF-BB and PCNA than the normal oxygen group (P<0.05).@*CONCLUSIONS@#Exogenous administration of PDGF-BB in neonatal rats with HPH may upregulate the expression of PCNA, promote pulmonary vascular remodeling, and increase pulmonary artery pressure.

Ultrasonic characteristics and histopathologic comparison of vascular remodeling after carotid balloon injury in rats / 中华超声影像学杂志

Objective:To detect the characteristics of vascular remodeling after carotid balloon injury model in rats using ultrasound biomicroscopy(UBM), and to discuss the application value of UBM technique by comparing ultrasonic characteristics with histopathological results.Methods:Carotid balloon injury was performed in 10-week-old SD rats(11 female and 11 male) by 2F Fogarty balloon catheter. The left common carotid artery(CCA) was injured and the right side in the same animal was used as an uninjured control. Arterial structures and hemodynamics were evaluated pre-procedure and post-procedure at 7, 14 days.The intima-media thickness(IMT) inner diameter, outer diameter, lumen area, vessel area, peak systolic velocity, end diastolic velocity of CCA were measured by UBM, and the vascular resistance index, shear stress and blood flow were calculated to evaluate the vascular hemodynamics. The histological data were obtained by H&E staining in cross-sections at 14 days after balloon injury. The characteristics of arterial structure and hemodynamic changes at various time points were compared, the structural changes of CCA between injured and control side after injury were compared. The Spearman correlation and linear regression were used to test the correlation between ultrasonic and histological measurements 14 days after balloon injury.Results:①Compared with pre-procedure, the IMT at 14 days after balloon injury was increased, the inner diameter was decreased, the shear stress in ultrasound was increased(all P<0.05). H&E staining histological test showed that IMT and neointima area in male rats were larger than those of female rats (all P<0.001). ②After carotid balloon injury, the lumen area decreased, but the CCA underwent compensatory positive remodeling and the vessel area increased. ③Significant correlations were demonstrated between UBM and histology in IMT, inner diameter, outer diameter and vessel area of CCA( rs=0.819, 0.965, 0.896, 0.955; all P<0.001). The vessel area value measured by UBM was larger than that of histology( P=0.006). Conclusions:The CCA of rats can be showed clearly by UBM in males and females. The arterial structure cab be measured by UBM accurately with good correlation with histology, as did arterial hemodynamic parameters, which may be benefit for the study in carotid balloon injury model of rats.

The mechanism of bone morphogenetic protein 2 regulating pulmonary vascular remodeling in pulmonary hypertension / 中国医师进修杂志

Objective:To explore the mechanism of bone morphogenetic protein 2 (BMP-2) regulating pulmonary vascular remodeling in pulmonary hypertension (PH).Methods:Pulmonary artery smooth muscle cells (PASMC) groups: control group, PH group, PH+BMP-2 group, PH+BMP-2+ small interfering BMP receptor(si-BMPR)-Ⅰa group, PH+BMP-2+ si-BMPR-Ⅰb group, PH+BMP -2+si-BMPR-Ⅱ group. In vitro PH model was induced by hypoxia. The three BMP-2 receptors were silenced by the transfection of si-BMPR-Ⅰa, si-BMPR-Ⅰb and si-BMPR-Ⅱ plasmids, respectively. Cell proliferation and apoptosis in each group were detected, transient receptor potential ion channel C1/6 (TRPC1/6), p21 mRNA and protein levels, and intracellular Ca 2+ concentration were detected. Results:The intracellular Ca 2+ concentration in the PH group was higher than that in the control group: (785.15 ± 44.26) nmol/L vs. (224.15 ± 15.87) nmol/L, the and apoptosis rate was lower than that in the control group: (3.15 ± 0.22)% vs. (7.31 ± 0.45)%, there were statistical differences ( P<0.05). The intracellular Ca 2+ concentration in the PH+BMP-2 group was (297.64 ± 21.46) nmol/L, and was lower than that in the PH group, and apoptosis rate was (6.88 ± 0.75)%, and was higher than that in the PH group, there were statistical differences ( P<0.05). The intracellular Ca 2+ concentration in the PH+BMP-2+si-BMPR-Ⅰa group, PH+BMP-2+ si-BMPR-Ⅰb group, PH+BMP -2+si-BMPR-Ⅱ group was (412.31 ± 29.57), (384.34 ± 30.66), (695.23 ± 39.85) nmol/L, and was higher than that in the PH+BMP-2 group, and apoptosis rate was (4.10 ± 0.27)%, (4.26 ± 0.28)%, (3.33 ± 0.24)%, and was lower than that in the PH+BMP-2 group, there were statistical differences ( P<0.05). The intracellular Ca 2+ concentration in the PH+BMP -2+si-BMPR-Ⅱ group was higher than that in the PH+BMP-2+si-BMPR-Ⅰa group and PH+BMP-2+ si-BMPR-Ⅰb group, the apoptosis rate was lower than that in the PH+BMP-2+si-BMPR-Ⅰa group and PH+BMP-2+ si-BMPR-Ⅰb group, there were statistical differences ( P<0.05). Conclusions:BMP-2 mainly inhibits the expression of TRPC1/6 by interacting with the receptor BMPR-Ⅱ, inhibits the influx of Ca 2+ and promotes the expression of p21, thereby inhibiting the proliferation of PASMC and promoting apoptosis, participating in pulmonary vascular remodeling in PH.

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-κB signaling pathway / 药学学报

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg·kg-1), and positive control sildenafil group (100 mg·kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% ± 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF-κB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF-κB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) by DYY.

Exposição a dieta hiperlipídica no período perinatal e pós desmame aumenta risco cardiometabólico e altera histomorfometria aórtica em ratos jovens / Exposure to high-fat diet in the perinatal and post-weaning period increases cardiometabolic risk and alters aortic histomorphometry in young rats

Introdução: estudos sugerem forte associação da exposição perinatal e pós-natal a dietas ricas em gordura e complicações cardiovasculares. Objetivo: avaliar os efeitos da exposição a dieta hiperlipídica no período perinatal e pós desmame sobre indicadores de risco cardiometabólico e alterações histomorfometrica na aorta em ratos. Metodologia: Ratas Wistar foram separadas em grupos de acordo com a dieta durante a gestação e lactação: dieta controle (n=3) e dieta hiperlipídica (n=3). No 21º dia de vida filhotes machos foram divididos em subgrupos (n=6): CC: formado por ratos expostos a dieta controle durante toda a vida; CH: formado por ratos cuja a mãe consumiu dieta controle e após o desmame os filhotes consumiram dieta hiperlipídica; HH: formado por filhotes expostos a dieta hiperlipídica durante toda a vida e HC: formado por ratos cuja a mãe consumiu dieta hiperlipídica e após o desmame os filhotes consumiram dieta controle. No 60º dia de vida, IMC, índices aterogênicos, proteína C reativa e histomorfometria da aorta dos descendentes foram avaliados. Resultados: o grupo HC apresentou maior IMC em comparação aos grupos HH e CH (p= 0,0004). A razão colesterol total / HDL-colesterol foi maior para o grupo CH comparado ao CC e HC (p = 0,016). Coeficiente aterogênico (p = 0,003), espessura da aorta (p = 0,003) e quantidade de lamelas elásticas (p = 0,0002) foram maiores nos grupos CH e HH em comparação a CC e HC. Conclusão: exposição a dieta hiperlipídica nos períodos perinatal e pós desmame aumentou o risco cardiometabólico e alterou a histomorfometria aórtica de ratos.

Background: studies suggest a strong association of perinatal and postnatal exposure to high-fat diets and cardiovascular complications. Objective: to evaluate the effects of exposure to a high-fat diet in the perinatal and post-weaning period on indicators of cardiometabolic risk and aorta histomorphometric changes in the rats. Methodology: Wistar rats were separated into groups according to the diet during pregnancy and lactation: control diet (n=3) and high fat diet (n=3). On the 21st day of life, male pups were divided into subgroups (n=6): CC: formed by rats exposed to a control diet for all life; CH: formed by rats whose mother consumed a control diet and after weaning the pups consumed a high-fat diet; HH: formed by pups exposed to a high-fat diet for all life and HC: formed by rats whose mother consumed a high-fat diet and after weaning the pups consumed a control diet. On the 60th day of life, BMI, atherogenic indices, C-reactive protein and histomorphometry of the aorta of the offspring were evaluated. Results: the HC group showed higher BMI compared to the HH and CH groups (p=0.0004). The total cholesterol / HDL-cholesterol ratio was higher for the CH group compared to CC and HC (p = 0.016). Atherogenic coefficient (p= 0,003), aortic thickness (p = 0.003) and amount of elastic lamellae (p = 0.0002) were higher in CH and HH groups compared to CC and HC. Conclusion: exposure to a high-fat diet in the perinatal and post-weaning periods increased cardiometabolic risk and altered aortic histomorphometry in rats.

Envelhecimento Vascular e Rigidez Arterial / Vascular Aging and Arterial Stiffness

Resumo O envelhecimento biológico é reflexo da interação entre genética, idade cronológica e fatores externos; é a base para novos conceitos em envelhecimento vascular, cuja progressão é determinada pela diferença entre idade biológica e cronológica. Do ponto de vista estrutural, os efeitos do envelhecimento vascular são mais evidentes na camada média das grandes artérias elásticas e resultam em aumento da rigidez arterial, da dilatação do lúmen e da espessura da parede. Esses efeitos são descritos no continuum de envelhecimento cardiovascular (proposto por Dzau em 2010) em que as etapas progressivas de lesões da microvasculatura de coração, rins e cérebro, têm início a partir do processo de envelhecimento. O aumento da rigidez arterial pode ser verificado de forma não invasiva por vários métodos. Os eventos cardiovasculares têm sido tradicionalmente previstos utilizando escores que combinam fatores de risco convencionais para aterosclerose. No continuum cardiovascular clássico (Dzau, 2006), é desafiador avaliar o peso exato da contribuição de cada fator de risco; entretanto, por refletir o dano precoce e cumulativo desses fatores de riscos cardiovascular, a rigidez arterial reflete o verdadeiro dano à parede arterial. Este artigo fornece uma visão geral dos mecanismos da fisiopatogenia, alterações estruturais das artérias e consequências hemodinâmicas do envelhecimento arterial; métodos não invasivos para a avaliação da rigidez arterial e da medida central da pressão arterial; o continuum de envelhecimento cardiovascular, e aplicação do conceito de rigidez arterial na estratificação de risco cardiovascular.

Abstract Biological aging occurs as a result of the interaction between genetics, chronological age and external factors. It is the basis for new concepts of vascular aging, whose progression is determined by the difference between biological and chronological age. From the structural point of view, the effects of vascular aging are more evident in the tunica media of large elastic arteries, marked by increased arterial stiffness, lumen dilation and wall thickness. These effects are described in the continuum of cardiovascular aging (proposed by Dzau in 2010), in which the progressive steps of microvasculature lesions of the heart, kidney and brain are initiated from the aging process. The increase of arterial stiffness can be detected by several non-invasive methods. Cardiovascular events have been traditionally described using scores that combine conventional risk factors for atherosclerosis. In the classic cardiovascular continuum (Dzau, 2006), to determine the exact contribution of each risk factor is challenging; however, since arterial stiffness reflects both early and cumulative damage of these cardiovascular risk factors, it is an indicator of the actual damage to the arterial wall. This article provides a general overview of pathophysiological mechanisms, arterial structural changes, and hemodynamic consequences of arterial stiffness; non-invasive methods for the assessment of arterial stiffness and of central blood pressure; the cardiovascular aging continuum, and the application of arterial stiffness in cardiovascular risk stratification.

Short isocapnic hyperoxia affects indices of vascular remodeling and intercellular adhesion molecules in healthy men

In preparation for tracheal intubation during induction of anesthesia, the patient may be ventilated with 100% oxygen. To investigate the impact of acute isocapnic hyperoxia on endothelial activation and vascular remodeling, ten healthy young men (24±3 years) were exposed to 5-min normoxia (21% O2) and 10-min hyperoxia trials (100% O2). During hyperoxia, intercellular adhesion molecules (ICAM-1) (hyperoxia: 4.16±0.85 vs normoxia: 3.51±0.84 ng/mL, P=0.04) and tissue inhibitor matrix metalloproteinase 1 (TIMP-1) (hyperoxia: 8.40±3.84 vs normoxia: 5.73±2.15 pg/mL, P=0.04) increased, whereas matrix metalloproteinase (MMP-9) activity (hyperoxia: 0.53±0.11 vs normoxia: 0.68±0.18 A.U., P=0.03) decreased compared to the normoxia trial. We concluded that even short exposure to 100% oxygen may affect endothelial activation and vascular remodeling.

Overview of miRNA involved in PASMCs phenotypic switching in pulmonary hypertension / 中国药理学通报

Pulmonary hypertension ( PH) is occult, with no distinctive clinical manifestations and poor prognosis.Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cell ( PASMCs) pheno- typic switching plays a crucial role.MicroRNA (miRNA) is a class of evolutionary highly conserved single-stranded small non-coding RNA.Recently, an increasing number of scholars have found that miRNA can play an important role in the occurrence and development of PH by regulating the phenotypic switching of PASMCs, which is expected to be a potential target for the prevention and treatment of PH.It has been found that miR NA such as miR-221 , miR-24, miR-15b, miR-96, miR-23a.miR-9, miR-214, miR-20a can promote the phenotypic switching of PASMCs, while miRNA such as miR-21, miR-132, miR-182, miR-449, miR-206 .miR-124, miR-30c, miR-140.miR-17-92 cluster can inhibit it.This article aims to review the research progress on miRNA that mediates PASMCs phenotypic switching in PH from both growth factor-related miRNA and hy- poxia-related miRNA.

Research progress on hypoxia-induced imbalance of calcium homeostasis in pulmonary artery smooth muscle cells and its treatment / 中国药理学通报

Chronic hypoxic lung diseases are major causes of disability and mortality worldwide, which are typically aggravated by hypoxic pulmonary hypertension.The pathogenesis of hypoxic pulmonary hypertension is complex, and its mechanism has not been fully elucidated.The previous studies have shown abnormally elevated levels of free Ca + in the cytoplasm of pulmonary artery smooth muscle cells to be the predominant drivers of pulmonary hypertension , causing continuous contraction and remodeling of the pulmonary vessels.This article briefly summarizes the mechanism of hypoxia-induced imbalance in calcium homeostasis in pulmonary artery smooth muscle cells, together with its related drug research, based on the existing literature.Hypoxia induces an imbalance in calcium homeostasis in pulmonary artery smooth muscle cells by regulating hypoxia-inducible factor-1, K+ , store-operated calcium channel, receptor-operated calcium channel, the Ca +-sensing myosin contractile mechanism by binding to calmodulin, leading to pulmonary vasoconstriction.Ca + can also activate PKC/ MAPKs and PI3K/Akt/mTOR pathways, leading to pulmonary vascular remodeling.

Research progress on mechanisms and therapeutic drugs of hypoxic pulmonary hypertension / 中国药理学通报

Hypoxic pulmonary hypertension ( HPH) is a complex mechanism of HPH is complex, and it has a high mortality rate cardiopulmonary disease eaused by hypoxia.The pathological of disability.Clinically the diug of treatment for HPH is unspe-cialized, mainly relying on traditional vasomotor dnrgs, inclu¬ding prostaglandin 12 receptor agonists, endothelin receptor an¬tagonists and phosphodiesterase-5 inhibitors, but their efficacy cannot be achieved.To meet the clinical need, it is of great sig¬nificance to develop targeted anti-HPH dnigs.To provide ideas for the discovery of HPH treatment drugs, the pathophysiological mechanism of HPH and the current status of dmg development are reviewed in the paper.

Research progress on therapeutic strategies for improving pulmonary vascular remodeling in pulmonary hypertension / 中国药理学通报

Pulmonary hypertension(PH)is a chronic,progressive,high-mortality disease characterized by a continuous increase in pulmonary vascular pressure. All types of PH have the same characteristics,i.e.,the excessive proliferation,anti-apoptosis and inflammation of pulmonary artery endothelial cells and smooth muscle cells,which leads to progressive thickening of pulmonary small vessels,resulting in pulmonary vascular remodeling and increased pulmonary vascular resistance,ultimately leading to right ventricular hypertrophy,heart failure,and death. The drugs used to treat PH mainly include L-type calcium channel blockers,phosphodiesterase 5 inhibitors,guanosine cyclase activators,endothelin receptor antagonists,and synthetic prostacyclin and its analogues. These drugs reduce pulmonary artery pressure by relaxing pulmonary blood vessels but do not cure the patient,and their prognosis remains poor. Therefore,the development of drugs that can effectively improve or even reverse pulmonary vascular remodeling is the key to treating PH. In recent years,studies on pulmonary vascular remodeling mainly included(1)the synthesis of new small-molecule compounds;(2)the transformation of mature drugs,such as the use of drug combinations and dosage form transformation,etc.;(3)the pharmacodynamic evaluation of traditional Chinese medicines and derived compounds based on the theory of "lung distension";(4)research into monomers of traditional Chinese medicine; and(5)research into new targets.

Progress of researches on schistosomiasis-associated pulmonary arterial hypertension / 中国血吸虫病防治杂志

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is categorized as WHO Group I PAH because its clinical manifestations, laboratory and hemodynamic features share with PAH of other etiologies, such as idiopathic, heritable, HIV and autoimmune disorders. Sch-PAH is usually a life-threatening complication of hepatosplenic schistosomiasis characterized by changes in the vascular wall, remodeling and vasoconstriction with lesions primarily located in the precapillary segments of the pulmonary vasculature, which may result in a marked and sustained increase in pulmonary vascular resistance, right ventricular failure and ultimately death. Although egg deposition into lung and subsequent inflammatory cascades are key factors in the pathogenesis of Sch-PAH, the exact pathogenesis, course of disease and treatment of Sch-PAH remain largely uncertain. This review mainly discusses the pathophysiological and immunological mechanisms of Sch-PAH, so as to provide insights into the clinical diagnosis and treatment of Sch-PAH.

Overwork Affects Extracellular Matrix of Arterial Vessel Wall in Rats / 中国医学科学院学报

Objective To explore the effect of overwork (OW) on extracellular matrix of arterial vessel wall in rats. Methods Random number grouping method was employed to assign 18 Sprague-Dawley rats into three groups(n=6):the control group(no special treatment),group OW(forced swimming twice a day for 15 days),and sleep deficiency(SD)+OW group(in addition to forced swimming twice a day,the rats were put on the platforms in water to limit sleep for 15 days).On the 16th day,the abdominal aorta and common carotid artery were collected after blood sampling from heart under deep anesthesia.A part of the abdominal aorta sample was taken for Masson staining of collagen fiber,and Verhoeff-Van Gieson staining was carried out for the elastic fiber of common carotid artery.Image J was employed for the quantitative analysis of collagen fiber and elastic fiber content.The expression of collagen 1(Col-1) protein was quantified by immunohistochemistry and the ultrastructure of vascular matrix was examined by transmission electron microscopy.The other part of the abdominal aorta sample was used to determine the mRNA levels of matrix metalloproteinase(MMP)-1,MMP-2,MMP-9,tissue inhibitor of metalloproteinases-1(TIMP-1),and Col-1 by quantitative real-time polymerase chain reaction. Results Compared with that in control group,the content of collagen fiber in groups OW and SD+OW had no significant change(all P>0.05);the content of elastic fiber in groups OW and SD+OW decreased(all P<0.001) and had no significant difference between each other(P>0.05).The vascular vessel wall of group OW showed slight fiber breakage,while that of group SD+OW presented wormhole-like or spongy fiber fragmentation.The mRNA levels of MMP-1 and MMP-2 in groups OW and SD+OW had no significant difference between each other(P>0.05) but were higher than that in control group(all P<0.001).The mRNA levels of MMP-9 and TIMP-1 had no significant difference among the three groups(all P>0.05).Groups OW and SD+OW had lower mRNA level(all P<0.001) and protein level(all P<0.001) of Col-1 than control group,while the mRNA and protein levels of Col-1 had no significant difference between groups OW and SD+OW(P>0.05). Conclusion OW can reduce the content of Col-1 and elastic fibers in the extracellular matrix of arterial vessels,destroy the elastic lamina of vascular wall,up-regulate the expression of MMP-1 and MMP-2,thereby injuring arterial vessels.