Journal of Vascular Research最新文献

Introduction: The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.

Methods: Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.

Results: Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility.

Conclusion: Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA.

Introduction: The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS.

Methods: Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates.

Results: Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractil

Introduction: Vascular smooth muscle cell (SMC) proliferation and vascular homeostasis are thought to be regulated by nitric oxide and prostaglandins. The loss of these endogenous mediators seems to play an important role for the development of restenosis following balloon angioplasty.

Methods: We examined the effect of exogenous linsidomine, a nitric oxide (NO) releasing compound, in a model of balloon injury iliac arteries of rabbits. On the cellular levels, NO can exert effects like cell survival, growth, and proliferation inhibition, has effects on transcription and proteasome effects and mitochondria-related effects in SMCs. SMC proliferation was quantified as a change of intima-media ratio. Linsidomine injection or its vehicle was performed with an infusion-balloon catheter directly into the dilated vessel wall.

Results: Balloon angioplasty resulted in a significant increase of intima-media ratio during the first 3 weeks. Linsidomine treatment decreased the intima-media ratio significantly compared to vehicle treated animals 3 weeks after balloon angioplasty (0.65 ± 0.05 vs 1.2 ± 0.2 intima-media ratio, p < 0.05). However, control vessels had an intima-media ratio of 0.15 ± 0.02. This effect was similar to NOS-2 transfected vessels following angioplasty. Immunohistochemical analysis demonstrated the expression of the proliferating cellular nuclear antigen in dilated vessel of vehicle treated animals, which was reduced in linsidomine-treated rabbits. In in vitro experiments, linsidomine inhibited significantly and dose-dependently rabbit SMC proliferation measured by BrdU incorporation. Further linsidomine increased rate of apoptotic SMCs, however, this effect was p53 independent.

Conclusion: Simultaneous angioplasty of the rabbit iliac artery and direct injection of linsidomine into the vessel wall seem to be an effective strategy to reduce neointima formation. Similar, local application of liposome encapsulation of human nitric oxide synthase-2 transfection resulted in potent inhibition of intima proliferation and SMC proliferation due to local restoration NO within the injured vasculature.

Introduction: Aortic aneurysm (AA) carries significant clinical implications due to its prevalence and potential complications. However, its etiopathogenesis remains poorly understood. The association between smoking and AA development has been consistently confirmed. Although AA was initially attributed to atherosclerosis, a negative association between diabetes (a major risk factor for atherosclerosis) and vascular aneurysmal disease has been observed. Investigating the biomechanical and histological properties of the aortic wall may shed light on the etiopathogenesis of aneurysms.

Methods: This study involved 75 Wistar rats, divided into four groups: control (CG), smoker (SG), diabetic (DG), and diabetic plus smoker (DSG). Rats in the SG and DSG groups were exposed to cigarette smoke for 30 min daily, 5 days a week. Diabetes was induced by intravenous injection of streptozotocin. After 16 weeks, the animals were sacrificed to collect the thoracic aorta. Destructive uniaxial tensile tests were performed to obtain the following biomechanical failure properties: force, tension, stress, strain, and strain energy. Histological analysis of these fragments consisted of the percentage evaluation of collagen and elastic fibers and verification of the magnitude of the inflammatory process in the arterial wall. Metalloproteinase-9 activity in the aortic specimens was quantified through zymography.

Results: Valid biomechanical tests of 36 specimens were analyzed, with 8 belonging to CG, 9 to DG, 11 to SG, and 8 to DSG. Biomechanical analysis of the fragments revealed that the maximum force and stress until rupture were lower in the DSG than in the SG with statistical significance. Evaluations of the percentage of collagen and elastic fibers as well as the inflammatory process showed no statistically significant difference among the groups studied. MMP-9 activity did not present a statistically significant difference among the different groups.

Conclusions: The biomechanical properties related to resistance are lower in DSG than in SG while elasticity, histological changes related to collagen fiber, elastic fiber, and inflammatory process, and MMP-9 activity of the aortic wall of rats do not show differences between CG and DG, SG, and DSG. Based on the methodology employed in this study, it appears that the thoracic aorta is resilient against aneurysm development.

Introduction: Heart failure (HF) and renal failure (RF) frequently coexist as cardiorenal syndrome, but their underlying causal mechanisms remain poorly defined.

Methods: This study applied Mendelian randomization (MR) using genome-wide association study (GWAS) datasets to investigate the causal effect of HF on RF. The inverse variance weighted method assessed causality, and summary-data-based MR (SMR) was used to identify therapeutic targets. Additional analyses included 211 gut microbiota traits and 1,400 serum metabolites. Validation was performed using the MIMIC-IV database. Transcriptomic data were analyzed to identify differentially expressed genes (DEGs) and key transcription factors (TFs).

Results: This study found that HF significantly increases the risk of RF (OR = 1.54, 95% CI: 1.07-2.23, p = 0.020). SMR analysis identified SURF1 and MAP3K11 as potential therapeutic targets for HF and RF. One gut microbiota genus and one serum metabolite showed causal associations with both diseases. MIMIC-IV data supported the HF-RF association (OR = 2.94, 95% CI: 2.81-3.07, p < 0.001). A total of 11 overlapping DEGs were enriched in the MAPK cascade, with RELA identified as a key TF.

Conclusion: This study provides genetic and molecular evidence supporting a causal role of HF in RF, highlighting microbial, metabolic, and immune mechanisms as potential therapeutic targets.

Introduction: Neutrophil infiltration is responsible for the neuroinflammation during an ischemic stroke. Here, we explored the role of receptor-interacting protein kinase 3 (RIP3) in neutrophil infiltration during an ischemic stroke.

Methods: The rat middle cerebral artery occlusion (MCAO) model was utilized to identify pivotal proteins involved in neutrophil infiltration during an ischemic stroke. Neutrophils were isolated from the peripheral blood of mice, and a co-immunoprecipitation (co-IP) assay was performed to identify the proteins that interact with RIP3.

Results: The rat MCAO model was successfully established. Myeloperoxidase (MPO) was significantly upregulated in the MCAO group, indicating the presence of neutrophil infiltration. RIP3 protein level exhibited a similar trend to MPO protein level, suggesting that neuroinflammation might be partly activated by RIP3 through the promotion of neutrophil infiltration. Co-IP and mass spectrometry analyses suggested that RIP3 facilitated neutrophil infiltration partly by affecting protein kinases (Rock1 and Prkaca) downstream of RIP3, and the interaction between RIP3 and Rock1 or Prkaca was validated by IF and co-IP assays.

Conclusion: In this study, it was observed that RIP3 affects neutrophil infiltration, a critical phenomenon associated with neuronal injury during ischemic stroke, partly by the modulation of downstream proteins such as Rock1 and Prkaca.

Introduction: Stress relaxation is considered a property of smooth muscle. Rings of thoracic aorta with/without perivascular adipose tissue (PVAT) stress relax. However, rings of isolated PVAT, containing no organized smooth muscle, also stress relax. We hypothesize that smooth muscle is not necessary in the individual tunicas of the aorta for stress relaxation to occur.

Methods: Histochemical staining and isometric contractility were performed on whole or tunicas of the thoracic aorta from the male and female Dahl salt-sensitive rats on normal diet. Masson trichrome and Verhoeff Van Gieson staining validated the isolation of the different tunicas. Stress relaxation was measured after cumulative amounts of passive tension were applied in the presence or absence of extracellular Ca2+, followed by challenge with the a1 adrenergic agonist phenylephrine (PE, 10-5 M).

Results: Stress relaxation occurred in all tunicas at each passive tension regardless of Ca2+. PE-induced contraction was observed in tissues containing smooth muscle (media, whole vessel) but not in the adventitia and aPVAT with Ca2+. No contraction was observed with no Ca2+.

Conclusions: All tunicas of the rat thoracic aorta stress relax, doing so without dependence on smooth muscle or Ca2+. PVAT demonstrated the greatest ability to stress relax.

Introduction: The aim of this study was to determine the effects of atorvastatin on cardiac function and hemodynamics and to investigate its functional mechanism on cardiac fibrosis in acute myocardial infarction (AMI) rats.

Methods: Cardiac functions and hemodynamic changes were evaluated in each group on day 28. Quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry were performed to detect the expression of notch1, transforming growth factor-β (TGF-β), Smad2, Smad7, as well as myocardial fibrosis factors (i.e., collagen I, collagen III, and galectin-3) in the myocardial tissues of AMI rats. The changes of myocardial cell structure and myocardial collagen fibers of AMI rats were observed with hematoxylin and eosin staining and Masson staining.

Results: Atorvastatin improved the cardiac function and hemodynamic performance. Atorvastatin downregulated the expression of notch1, smad2, collagen I, and collagen III in AMI rats. Atorvastatin treatment decreased the transcription of notch1, TGF-β, and smad2, while it increased smad7 in AMI rats. Atorvastatin induced the downregulation of collagen I, collagen III, and galectin-3. Myocardial immunohistochemical analysis showed atorvastatin inhibited the expression of notch1, TGF-β, and smad2 in myocardial tissues.

Conclusion: Atorvastatin inhibited myocardial fibrosis by interfering with notch1-TGF-β-smads signal pathways. In addition, it could mitigate myocardial remodeling and improve cardiac functions and hemodynamics.

Introduction: Control of blood pressure following acute type B aortic dissection usually requires sympatholytic antihypertensive medication. Although sympathetic nerve activity is central to blood pressure control, its role in the hypertensive response to acute aortic dissection has not been assessed.

Methods: A prospective pilot study was performed over an 18-month period. Patients presenting with acute type B aortic dissection confirmed on computed tomographic angiography were recruited. We measured blood pressure, heart rate, muscle sympathetic nerve activity (MSNA), and plasma catecholamine levels in patients following acute type B dissection and controls. Comparisons between groups were made 1 week (acute phase) and 3 months after dissection (recovery phase).

Results: Five patients and four controls were recruited in the study. MSNA was higher in patients than controls during the acute phase of aortic dissection: 62 (60-62) versus 46 (29-60) bursts/min (effect size 0.88) and 88 (54-96) versus 71 (44-101) bursts/100 beats (effect size 0.60). Plasma normetanephrines were also increased acutely: 821.0 (489.0-884.0) versus 417.0 (348.5-561.5) pmol/L (effect size 0.85).

Conclusion: Sympathetic nerve activity is increased acutely during the first week after type B aortic dissection, resolving towards control values after 3 months. Immediate sympatholytic drug treatment is likely to be crucial in order to prevent the acute and chronic complications of this response. This may confer benefits over and above simply lowering the blood pressure to protect the aorta in the acute phase.

Introduction: Although it is well-known that patients with high bleeding risk (HBR) who undergo percutaneous coronary intervention (PCI) have poor clinical outcomes, the details have not been fully clarified for acute coronary syndrome (ACS) population. The aim of this study was to describe patient and lesion characteristics in patients with ACS and HBR as defined by the Academic Research Consortium (ARC).

Methods: Patients with ACS (n = 961) who underwent optical coherence tomography (OCT)-guided PCI were investigated. They were divided into HBR and non-HBR groups according to the ARC HBR criteria. Clinical background, lesion characteristics on angiography and OCT, and clinical outcomes during the 2-year follow-up period were compared between the groups.

Results: The HBR group comprised 307 patients (32%). The frequency of multi-vessel coronary disease was higher in the HBR group than the non-HBR group (34% vs. 26%, p = 0.015). OCT findings demonstrated a higher frequency of calcified nodules as the underlying pathology for ACS in the HBR group (12% vs. 3%, p < 0.001), with a correspondingly higher frequency of calcified plaques (55% vs. 39%, p < 0.001). Kaplan-Meier estimates of the incidence of major bleeding (11.0% vs. 2.4%, p < 0.001) and cardiac death (8.5% vs. 2.4%, p < 0.001) were more prevalent for the HBR group than the non-HBR group during the follow-up period.

Conclusion: ACS patients with HBR factors had more advanced atherosclerosis which contributed to a higher prevalence of cardiac death as well as major bleeding complications.

Introduction: Endogenous biological timing mechanisms are fundamental aspects of living cells, tissues, and organisms. Virtually every aspect of physiology and behavior is mediated by self-sustaining circadian clocks, which depend on light to synchronize with the external daily environment. However, exposure to artificial light at night (ALAN) can impair temporal adaptations and affect health and disease.

Methods: During a study of the effects of long-term ALAN exposure on cardiovascular function, we serendipitously detected ultradian rhythms in muscarinic receptor dependent relaxation of isolated aortic tissue.

Results and conclusion: Mice exposed to dark nights displayed an ultradian pattern of maximum endothelial-dependent relaxation that was antiphase between the sexes. Rhythmic patterns of relaxation were abolished by ALAN exposure in both sexes suggesting that ALAN exposure can affect ultradian rhythms in physiology and behavior.