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.

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.

Research progress on the mechanism of phenotypic transformation of pulmonary artery smooth muscle cells induced by hypoxia / 浙江大学学报·医学版

Phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) is a key factor in pulmonary vascular remodeling. Inhibiting or reversing phenotypic transformation can inhibit pulmonary vascular remodeling and control the progression of hypoxic pulmonary hypertension. Recent studies have shown that hypoxia causes intracellular peroxide metabolism to induce oxidative stress, induces multi-pathway signal transduction, including those related to autophagy, endoplasmic reticulum stress and mitochondrial dysfunction, and also induces non-coding RNA regulation of cell marker protein expression, resulting in PASMCs phenotypic transformation. This article reviews recent research progress on mechanisms of hypoxia-induced phenotypic transformation of PASMCs, which may be helpful for finding targets to inhibit phenotypic transformation and to improve pulmonary vascular remodeling diseases such as hypoxia-induced pulmonary hypertension.

Atorvastatina Atenua o Remodelamento Vascular em Camundongos com Síndrome Metabólica / Atorvastatin Attenuates Vascular Remodeling in Mice with Metabolic Syndrome

Resumo Fundamento A síndrome metabólica é caracterizada por um conjunto de comorbidades. Durante a síndrome, observam-se alterações estruturais no sistema cardiovascular, especialmente o remodelamento vascular. Uma das causas predisponentes para essas alterações é a inflamação crônica oriunda de mudanças na estrutura e composição do tecido adiposo perivascular. Atorvastatina é eficaz no tratamento das dislipidemias. No entanto, seus efeitos pleiotrópicos não são totalmente compreendidos. Supõe-se que, durante a síndrome metabólica, ocorre remodelamento vascular e que o tratamento com atorvastatina pode ser capaz de atenuar tal condição. Objetivos Avaliar os efeitos do tratamento com atorvastatina sobre o remodelamento vascular em modelo experimental de síndrome metabólica. Métodos Camundongos Swiss receberam dieta controle ou dieta hiperglicídica por 18 semanas. Após 14 semanas de dieta, os camundongos foram tratados com veículo ou atorvastatina (20mg/kg) durante 4 semanas. Foram avaliados o perfil nutricional e metabólico por testes bioquímicos; análise estrutural da artéria aorta por histologia e dosagem de citocinas por ensaio imunoenzimático. O nível de significância aceitável para os resultados foi p <0,05. Resultados A dieta hiperglicídica promoveu o desenvolvimento de síndrome metabólica. Tal fato culminou no remodelamento hipertrófico do músculo liso vascular e tecido adiposo perivascular. Além disso, houve aumentos das citocinas TNF-α e IL-6 circulantes e no tecido adiposo perivascular. O tratamento com atorvastatina reduziu significativamente os danos metabólicos, o remodelamento vascular e os níveis de citocinas. Conclusão Atorvastatina ameniza danos metabólicos associados à síndrome metabólica induzida por dieta hiperglicídica, além de atenuar o remodelamento vascular, sendo esses efeitos associados à redução de citocinas pró-inflamatórias.

Abstract Background Metabolic syndrome is characterized by an array of comorbidities. During this syndrome, structural changes are observed in the cardiovascular system, especially vascular remodeling. One of the predisposing causes for these changes is chronic inflammation resulting from changes in the structure and composition of perivascular adipose tissue. Atorvastatin is effective in the treatment of dyslipidemias. However, its pleiotropic effects have not been completely understood. We hypothesize that metabolic syndrome may lead to vascular remodeling and that atorvastatin therapy may be able to attenuate this condition. Objectives To assess the effects of atorvastatin therapy on vascular remodeling in an experimental model of metabolic syndrome. Methods Swiss mice received a control diet or a hyperglicemic diet for 18 weeks. After 14 weeks of diet, mice were treated with vehicle or atorvastatin (20mg/kg) during for 4 weeks. Nutritional and metabolic profiles were assessed by biochemical tests; moreover, a histological assessment of aorta structure was conducted, and cytokine levels were determined by the immunoenzyme assay. The acceptable level of significance for the results was set at p<0.05. Results Hyperglicemic diet promoted the development of metabolic syndrome. It indeed culminated in hypertrophic remodeling of vascular smooth muscle and perivascular adipose tissue. Furthermore, there were increases in the levels of circulating TNF-α and IL-6 and in the perivascular adipose tissue. Atorvastatin therapy significantly reduced metabolic damages, vascular remodeling, and cytokine levels. Conclusion Atorvastatin attenuate metabolic damages associated with metabolic syndrome induced by hyperglycemic diet, in addition to attenuating vascular remodeling; both effects are associated with reduced levels of pro-inflammatory cytokines.

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

OBJECTIVE@#To study the role of vascular endothelial growth factor-A (VEGF-A) in pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH) by regulating survivin (SVV).@*METHODS@#A total of 96 neonatal rats were randomly divided into three groups: HPH+VEGF-A group, HPH group, and control group. Each group was further randomly divided into 3-, 7-, 10-, and 14-day subgroups (@*RESULTS@#The HPH group had a significantly higher mean RVSP than the control and HPH+VEGF-A groups at each time point (@*CONCLUSIONS@#Prophylactic intratracheal administration of exogenous VEGF-A in neonatal rats with HPH can inhibit pulmonary vascular remodeling and reduce pulmonary arterial pressure by upregulating the expression of SVV in the early stage of hypoxia. This provides a basis for the interventional treatment of pulmonary vascular remodeling in neonatal HPH.

New insights into vascular mechanobiology: roles of matrix mechanics in regulating smooth muscle cell function / 生理学报

Vascular smooth muscle cell (vSMC) is the predominant cell type in the blood vessel wall and is constantly subjected to a complex extracellular microenvironment. Mechanical forces that are conveyed by changes in stiffness/elasticity, geometry and topology of the extracellular matrix have been indicated by experimental studies to affect the phenotype and function of vSMCs. vSMCs perceive the mechanical stimuli from matrix via specialized mechanosensors, translate these stimuli into biochemical signals controlling gene expression and activation, with the consequent modulation in controlling various aspects of SMC behaviors. Changes in vSMC behaviors may further cause disruption of vascular homeostasis and then lead to vascular remodeling. A better understanding of how SMC senses and transduces mechanical forces and how the extracellular mechano-microenvironments regulate SMC phenotype and function may contribute to the development of new therapeutics for vascular diseases.

Roles of smooth muscle 22α in vascular homeostasis and vascular remodeling / 生理学报

The research on the molecular mechanism of vascular injury has been a hot topic in recent years since the mechanism can be targeted for the treatment of vascular injury diseases. A large number of studies have found that vascular injury, repair and pathological remodeling are closely related to phenotype switching, abnormal proliferation and migration, and apoptosis of vascular smooth muscle cells (VSMCs). Smooth muscle 22α (SM22α) is a shape change and transformation sensitive F-actin-binding protein. SM22α decorates the contractile filament bundles within cultured VSMCs exhibiting differentiated phenotypes. In addition, SM22α is involved in regulation of cell signaling pathways related to vascular homeostasis and vascular remodeling. Here, we reviewed the recent research progress of SM22α in vascular homeostasis and remodeling.

Rigidez arterial: um novo fator de risco cardiovascular / Arterial stiffness: a novel cardiovascular risk factor

A avaliação precisa do risco cardiovascular é essencial para a tomada de decisão clínica. O objetivo do tratamento da hipertensão arterial é reduzir a morbimortalidade, prevenindo danos aos órgãos-alvo. As lesões subclínicas consistem em uma apresentação precoce da doença cardiovascular sem manifestações clínicas aparentes. Os eventos cardiovasculares futuros têm sido tradicionalmente previstos utilizando escores que combinam fatores de risco para aterosclerose convencionais. O aumento da velocidade da onda de pulso (VOP) é um biomarcador padrão-ouro do enrijecimento arterial, e pode avaliar o risco cardiovascular prospectivo e de mortalidade, além de identificar danos aos órgãos e orientar início de tratamento precoce. Efetivamente, os valores da VOP podem reclassificar o risco cardiovascular para um valor mais alto, especialmente em indivíduos mais jovens com risco intermediário. A idade vascular pode ser maior que a idade cronológica, devido aos fatores de risco. O envelhecimento arterial pode resultar em três padrões atualmente estudados: EVA (early vascular aging) - indivíduos com envelhecimento arterial precoce; HVA (healthy vascular aging) - indivíduos com envelhecimento arterial saudável e SUPERNOVA - indivíduos com envelhecimento arterial extremamente baixo para a sua idade. Assim, a avaliação do envelhecimento vascular fundamentado somente nos fatores de risco cardiovasculares pode falhar, enquanto a VOP representa o dano cumulativo de todos esses fatores na parede arterial. No entanto, existe uma lacuna entre o potencial benefício clínico da avaliação da rigidez arterial e a prática de subutilização no mundo real. Ferramentas clínicas vem sendo desenvolvidas para prever níveis elevados de VOP e identificar pacientes que devem ter a rigidez arterial avaliada.

Accurate cardiovascular risk assessment is essential for clinical decision-making. The purpose of treating hypertension is to reduce morbidity and mortality, preventing damage to target organs. Subclinical lesions consist of an early presentation of cardiovascular disease with no apparent clinical manifestations. Future cardiovascular events have traditionally been predicted using scores that combine conventional risk factors for atherosclerosis. Increased pulse wave velocity (PWV) is a gold standard biomarker of arterial stiffness, and can assess prospective cardiovascular risk and mortality, identify organ damage and guide early treatment. In fact, PWV can reclassify cardiovascular risk to a higher value, especially in younger individuals with intermediate risk. Vascular age may be greater than chronological age due to risk factors. Arterial aging can result in three patterns currently under study: EVA (early vascular aging) ­ individuals with early arterial aging; HVA (healthy vascular aging) ­ individuals with healthy arterial aging and SUPERNOVA ­ individuals with extremely low arterial aging for their age. Thus, the evaluation of vascular aging solely based on cardiovascular risk factors may fail, while PWV represents the cumulative damage of all these factors on the arterial wall. However, there is a gap between the potential clinical benefit of assessing arterial stiffness and underutilization in the real world. Clinical tools have been developed to predict high levels of PWV and to identify patients who should have their arterial stiffness assessed.

Cellular Senescence in Arterial Diseases

Cell-proliferation potency is limited, as cells cannot proceed through the cell cycle continually. Instead, they eventually show an irreversible arrest of proliferation, commonly referred to as cellular senescence. Following the initial discovery of this phenomenon by Hayflick et al., studies have indicated that cells are also destined to undergo aging. In addition to the irreversible termination of proliferation, senescent cells are characterized by a flattened and enlarged morphology. Senescent cells become pro-inflammatory and contribute to the initiation and maintenance of sustained chronic sterile inflammation. Aging is associated with the accumulation of senescent cells in the cardiovascular system, and in general these cells are considered to be pathogenic because they mediate vascular remodeling. Recently, genetic and pharmacological approaches have enabled researchers to eliminate senescent cells both in vitro and in vivo. The term “senolysis” is now used to refer to the depletion of senescent cells, and evidence indicates that senolysis contributes to the reversal of age-related pathogenic phenotypes without the risk of tumorigenesis. The concept of senolysis has opened new avenues in research on aging, and senolysis may be a promising therapeutic approach for combating age-related disorders, including arterial diseases.

Canonical Transient Receptor Potential Channels and Vascular Smooth Muscle Cell Plasticity

Vascular smooth muscle cells (VSMCs) play a pivotal role in the stability and tonic regulation of vascular homeostasis. VSMCs can switch back and forth between highly proliferative (synthetic) and fully differentiated (contractile) phenotypes in response to changes in the vessel environment. Abnormal phenotypic switching of VSMCs is a distinctive characteristic of vascular disorders, including atherosclerosis, pulmonary hypertension, stroke, and peripheral artery disease; however, how the control of VSMC phenotypic switching is dysregulated under pathological conditions remains obscure. Canonical transient receptor potential (TRPC) channels have attracted attention as a key regulator of pathological phenotype switching in VSMCs. Several TRPC subfamily member proteins—especially TRPC1 and TRPC6—are upregulated in pathological VSMCs, and pharmacological inhibition of TRPC channel activity has been reported to improve hypertensive vascular remodeling in rodents. This review summarizes the current understanding of the role of TRPC channels in cardiovascular plasticity, including our recent finding that TRPC6 participates in aberrant VSMC phenotype switching under ischemic conditions, and discusses the therapeutic potential of TRPC channels.

NF-κB inhibitor improves pulmonary vascular remodeling by reversing LPS-induced down-regulation of BMPRII / 生理学报

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation of bone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB (NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-induced pulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 μg/mL of LPS. The expression levels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal (i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells were detected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in the MCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expression in human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 μmol/L) reversed the effect of LPS. In the pulmonary artery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratio of right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantly increased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonary vessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAH model rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promoting the occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.

Sexo e idade e sua influência sobre a anatomia da aorta abdominal e seus ramos / Age and sex and their influence on the anatomy of the abdominal aorta and its branches

Resumo Contexto Não se sabe ao certo como a idade e o sexo do paciente influenciam na anatomia da aorta abdominal e de seus ramos. Objetivos Determinar os padrões anatômicos (diâmetro e angulações) mais frequentes da aorta abdominal e de seus ramos e a influência do sexo e da idade dos pacientes sobre esses padrões. Métodos Foram avaliadas tomografias computadorizadas de abdome com contraste endovenoso de 157 pacientes. Foram aferidos calibre e angulação de artérias abdominais em indivíduos de ambos os sexos, agrupados em cinco faixas etárias: 20 a 30 anos, 31 a 40 anos, 41 a 50 anos, 51 a 60 anos e 61 a 70 anos. Foram analisadas 18 variáveis: seis ângulos de emergências arteriais, nove diâmetros arteriais, taxas de dilatação, sexo e faixa etária. Para a obtenção das medidas, utilizou-se o programa de computador RadiAnt 4.2.1 DICOM viewer (Medixant, Poznan, Polônia). Resultados Entre as 157 tomografias, 69 eram de homens e 88, de mulheres. Apresentaram diferença estatística (p < 0,05): ângulo de origem e diâmetro da artéria mesentérica superior; ângulo e diâmetro das artérias renais; diâmetro das artérias ilíacas comuns; diâmetro e taxa de dilatação em diversos segmentos da aorta, exceto na porção proximal ao tronco celíaco. Conclusões Os diâmetros da aorta (em diversos segmentos) e de seus ramos (exceto da artéria renal esquerda) aumentam progressivamente com o passar da idade em ambos os sexos e são maiores e possuem taxa de dilatação mais elevada em homens do que em mulheres da mesma faixa etária. Entre os sexos, o ângulo de emergência da artéria mesentérica superior foi maior em homens, exceto entre 20 e 30 anos; o ângulo de origem da artéria renal esquerda foi maior em mulheres entre 51 e 60 anos.

Abstract Background It is not clear how patients' age and sex influence the anatomy of the aorta and its branches. Objectives To determine the most frequent anatomical patterns of diameter and angulation of the abdominal aorta and its branches and the influence of patients' sex and age on these patterns. Methods CT scans with intravenous contrast from 157 patients were analyzed. Diameter and angulations of the abdominal aorta and its branches were measured in individuals of both sexes, classified into five age groups: 20 to 30 years, 31 to 40 years, 41 to 50 years, 51 to 60 years, and 61 to 70 years. Eighteen variables were analyzed: 6 arterial origin angles, 9 arterial diameters, rate of diameter enlargement, and patient's sex and age. RadiAnt 4.2.1 DICOM viewer software was used for measurements. Results The total of 157 CT scans were from 69 men and 88 women. There were statistical differences (p <0.05) in the following results: angle of origin and diameter of the superior mesenteric artery; renal artery angle and diameter; diameter of the common iliac arteries, and diameter and rate of diameter enlargement of the aorta in several segments, but not the segment immediately proximal to the celiac trunk. Conclusions The diameters of several aorta segments and of its branches (except the left renal artery) increase progressively with age in both sexes and are larger and have a higher rate of diameter enlargement in men than in women in the same age ranges. Between sexes, the angle of origin of the superior mesenteric artery was larger in men, except between 20 and 30 years, and the angle of origin of the left renal artery was larger in women between 51 and 60 years old.

The expression and meaning of Hippo signaling pathway in carotid artery ligation induced arterial remodeling model of rats / 中国应用生理学杂志

OBJECTIVE@#To establish an arterial remodeling model of rats and to investigate the expression and role of Hippo signaling pathway in this model.@*METHODS@#In the model group (n=40), the left common carotid artery was removed through the median incision of the neck. The 6-0 non-absorbable line was used to ligate the carotid artery near the proximal end as far as possible, completely blocking the blood flow. The common carotid artery of rats in control group (n=20) was not ligated using the operative line. After 14 days, the animals were sacrificed and the common carotid arteries were separated through the original surgical pathway and the arteries from the ligature to the distal end were collected. Arterial morphology and fibrosis were observed by HE and MASSON staining. Immunohistochemical staining was used to detect the expressions of anti-α smooth muscle actin (α-MSA) and proliferating cell nuclear antigen (PCNA) in the carotid artery. Western blot was used to detect the expressions of yes associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), TEAD1, Bcl-2-like protein 4 (Bax), and B-cell lymphoma-2 (Bcl-2).@*RESULTS@#Compared with the control group, the HE staining showed that the vascular remodeling was obvious, the ratio of the neointima/middle membrane was increased significantly, and the MASSON staining indicated that the fibrosis was significantly increased in model group. The immunohistochemical staining suggested that the expressions of α-SMA and PCNA were increased significantly; Western blot suggested that the expressions of YAP, TAZ, TEAD1, and Bcl-2 were increased in carotid artery of the model group. While the expression of Bax and the ratio of Bax/Bcl-2 were decreased.@*CONCLUSION@#A rat model of arterial remodeling mediated by carotid artery ligation was established successfully in this study. Hippo signaling pathway was proved to be activated in the arterial remodeling model induced by carotid artery ligation in rats, and might regulate the change of Bax/Bcl-2 ratio related to proliferation and apoptosis, and subsequently involved in the proliferation of smooth muscle cells to promote vascular remodeling.

Effects of apple polyphenols on monocrotaline-induced pulmonary vascular remodeling in rats and its mechanism / 中国应用生理学杂志

OBJECTIVE@#To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism.@*METHODS@#Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined.@*RESULTS@#Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05).@*CONCLUSION@#MCT can increase COX-2 expression and intracellular Ca in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.

Pericyte Plasticity in the Brain / 神经科学通报·英文版

Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.

Advances in molecular mechanism of vascular remodeling in pulmonary arterial hypertension / 浙江大学学报·医学版

Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH,and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.

tPA Helpers in the Treatment of Acute Ischemic Stroke: Are They Ready for Clinical Use? / 대한뇌졸중학회지

Tissue plasminogen activator (tPA) is the only therapeutic agent approved to treat patients with acute ischemic stroke. The clinical benefits of tPA manifest when the agent is administered within 4.5 hours of stroke onset. However, tPA administration, especially delayed administration, is associated with increased intracranial hemorrhage (ICH), hemorrhagic transformation (HT), and mortality. In the ischemic brain, vascular remodeling factors are upregulated and microvascular structures are destabilized. These factors disrupt the blood brain barrier (BBB). Delayed recanalization of the vessels in the presence of relatively matured infarction appears to damage the BBB, resulting in HT or ICH, also known as reperfusion injury. Moreover, tPA itself activates matrix metalloproteases, further aggravating BBB disruption. Therefore, attenuation of edema, HT, or ICH after tPA treatment is an important therapeutic strategy that may enable clinicians to extend therapeutic time and increase the probability of excellent outcomes. Recently, numerous agents with various mechanisms have been developed to interfere with various steps of ischemia/reperfusion injuries or BBB destabilization. These agents successfully reduce infarct volume and decrease the incidence of ICH and HT after delayed tPA treatment in various animal stroke models. However, only some have entered into clinical trials; the results have been intriguing yet unsatisfactory. In this narrative review, I describe such drugs and discuss the problems and future directions. These “tPA helpers” may be clinically used in the future to increase the efficacy of tPA in patients with acute ischemic stroke.

Molecular mechanism of vascular remodeling in hypertension and Chinese medicine intervention / 生理学报

Vascular remodeling is a significant pathological characteristic of hypertension, which is regulated by complex regulatory networks. The vascular remodeling may be adaptive initially, however it becomes maladaptive and decompensation eventually and further compromises target organ function, leading to hypertensive cardiovascular complications. This review focuses on the role and mechanisms of vascular remodeling in the pathogenesis and progression of hypertension and its complications. Moreover, the strategies of syndrome differentiation of traditional Chinese medicine application provide clinical and theoretical evidences for hypertensive vascular remodeling therapy. A better understanding of underlying signaling pathways, therapeutic targets in vascular remodeling, as well as screening of active ingredients from traditional Chinese medicine may be able to provide some effective approaches for vascular protection in hypertensive diseases.

Effects of Ramipril on the expression of connexin 43 in cerebral arteries of spontaneously hypertensive rats / 生理学报

The present study was designed to examine whether Ramipril (an inhibitor of angiotensin-converting enzyme) affected spontaneous hypertension-induced injury of cerebral artery by regulating connexin 43 (Cx43) expression. Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were randomly divided into WKY, WKY + Ramipril, SHR, and SHR + Ramipril groups (n = 8). The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography. Hematoxylin-eosin (HE) staining was used to show vascular remodeling. The expression and distribution of Cx43 was determined by using immunofluorescence and immunohistochemistry analysis. The protein and mRNA levels of Cx43 were examined by Western blot and real-time PCR analysis, respectively. The results showed that chronic Ramipril treatment significantly attenuated blood pressure elevation (P < 0.01, n = 8) and blood vessel wall thickness in SHR (P < 0.01, n = 8). The cerebral artery contraction rate in the SHR group was higher than that in the WKY group (P < 0.05, n = 8). The cerebral artery contraction rate in the SHR + Ramipril group was lower than that in the SHR group (P < 0.05, n = 8). Pretreatment with 2-APB (Cx43 non-specific blocker) or Gap26 (Cx43 specific blocker) significantly decreased the vasoconstriction rate, while pretreatment with AAP10 (Cx43 non-specific agonist) significantly increased the vasoconstriction in the SHR + Ramipril group (P < 0.05, n = 8). In addition, the expression of Cx43 mRNA and protein in cerebral arteries of SHR group was higher than that of WKY group (P < 0.05, n = 8). The mRNA and protein expression of Cx43 in cerebral arteries of SHR + Ramipril group was significantly lower than that of SHR group (P < 0.05, n = 8). These results suggest that Ramipril can down-regulate the expression of Cx43 mRNA and protein in cerebral arterial cells of SHR, lower blood pressure, promote vasodilation, and improve arterial damage and vascular dysfunction caused by hypertension.

Expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/Tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary diseases and their relationships with pulmonary vascular remodelling

SUMMARY OBJECTIVE: This study aims at investigating the expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary disease (COPD) and their relationships with pulmonary vascular remodelling (PVR). METHODS: 60 para-tumour tissues were divided into the COPD group and the control group (n=30); the inflammations, pulmonary artery wall area/total artery area (WA%), and wall thickness/vascular outer diameter (WT%) were compared. The expressions of TLR-4, MMP-9/TIMP-1, and PCNA in pulmonary vascular smooth muscle cells were detected, and their relationships with PVR were then analysed. RESULTS: The inflammations (1.6±0.8), WA% (44.0±6.4), and WT% (27.3±3.3) in the COPD group were higher than in the control group (0.3±0.5, 26.1±2.8, 15.6±1.8), and the expressions of TLR-4 (31.4±147) and MMP-9/TIMP-1 (2.2±2.6) were increased compared to the control group (4.7±4.5, 1.9±12). Correlation analysis: TLR-4 and MMP-9/TIMP-1 were positively correlated with the inflammations (r=0.18, P<0.01), WA% (r=0.68, P<0.01), and WT% (r=0.73, P<0.01), as well as positively correlated with the expression of PCNA (r=0.44, P<0.01); the upregulation of TLR-4 was positively correlated with the expressions of MMP-9 and TIMP-1. CONCLUSIONS: The upregulation of TLR-4 in the pulmonary arterial smooth muscle cells of COPD patients could promote the inflammations and the MMP-9 expression, thus causing abnormal degradation of extracellular matrix, so it played an important role in the process of PVR.

RESUMO OBJETIVO: Este estudo tem como objetivo investigar as expressões de TOLL-like receptor 4 (TLR-4) e metaloproteinase 9 da matriz (MMP-9)/inibidor de tecido da metaloproteinase 1 (TIMP-1) em vasos sanguíneos pulmonares com doença pulmonar obstrutiva crônica (DPOC) e suas relações com o remodelamento vascular pulmonar (PVR). MÉTODOS: Sessenta tecidos paratumorais foram divididos em grupo COPD e o grupo controle (n = 30). Foram comparadas as inflamações, área da parede da artéria pulmonar/área da artéria total (WA%) e espessura da parede/diâmetro externo vascular (WT%). As expressões de TLR-4, MMP-9/TIMP-1 e PCNA em células de músculo liso vascular pulmonar foram detectadas, e suas relações com PVR foram então analisadas. RESULTADOS: As inflamações (1,6 ± 0,8), WA% (44,0 ± 6,4) e WT% (27,3 ± 3,3) no grupo COPD foram maiores que no grupo controle (0,3 ± 0,5; 26,1 ± 2,8; 15,6 ± 1,8). E as expressões de TLR-4 (31,4 ± 14,7) e MMP-9/TIMP-1 (2,2 ± 2,6) foram aumentadas em relação ao grupo controle (4,7 ± 4,5, 1,9 ± 1,2). Na análise de correlação, TLR-4 e MMP-9/TIMP-1 foram positivamente correlacionadas com as inflamações (r = 0,18; P <0,01), WA% (r = 0,68; P <0,01) e WT% (r = 0,73; P <0,01), bem como correlacionadas positivamente com a expressão de PCNA (r = 0,44; P <0,01). A elevação da TLR-4 foi correlacionada positivamente com as expressões de MMP-9 e TIMP-1. CONCLUSÕES: A regulação positiva do TLR-4 nas células do músculo liso arterial pulmonar de pacientes com DPOC poderia promover as inflamações e a expressão de MMP-9, causando assim uma degradação anormal da matriz extracelular, por isso desempenhou um papel importante no processo de PVR.