Journal of Vascular Research最新文献

Introduction: Inflammatory pathways in vascular disease are the focus of intense interest. Multiple studies have shown that interleukin-6 (IL-6) is strongly implicated in the atherosclerotic process. Accumulating evidence suggests a similar role for growth differentiation factor-15 (GDF-15).

Methods: In this study, we measured and compared circulating levels of IL-6 and GDF-15 in a cohort of 20 vascular surgical patients with atherosclerotic disease presenting for surgical revascularization (carotid endarterectomy or common femoral artery endarterectomy) and in a similar number of age-matched healthy volunteers. A cross-sectional analysis of prospectively collected data was performed, with serum GDF-15 and IL-6 levels measured and assessed using enzyme-linked immunosorbent assays (ELISAs).

Results: We observed substantial circulating levels of GDF-15 in most patients (17/20) compared to the reference range upper limit of 1,500 pg/mL, irrespective of the type of vascular disease and revascularization procedure they were undergoing. In contrast, only 1 healthy control participant had a borderline high GDF-15 of 1,572 pg/mL. Indeed, the mean serum GDF-15 level between patients (2,515 pg/mL, SD 906) and healthy controls (1,016 pg/mL, SD 219) was highly significant (p value <0.001). On the other hand, although IL-6 levels between patients (mean 3.6, SD 2.54 pg/mL) and healthy controls (mean 2.2, SD 0.67 pg/mL) were significantly different (p = 0.020), only 7 patients had values above the reference range upper limit of 3.4 pg/mL.

Conclusion: These results suggest that serum GDF-15, but not IL-6, is a strong candidate for use as a biomarker of atherosclerotic vascular disease and may allow for earlier risk factor modification to help prevent disease onset and progression. Large-scale studies aimed at determining whether a rising GDF-15 is an indication of worsening outcome in a wider spectrum of patients with vascular disease are clearly warranted.

Introduction: We describe methods by which vasomotion can be recorded in awake and anesthetized human subjects without significant interference from other spontaneous vascular oscillations.

Methods: In three separate studies, we used photoplethysmography (PPG) to record vasomotion in fingertips. In Study 1, we induced chemical sympathectomy in the studied hand of 11 awake subjects who received intravenous dexmedetomidine infusions. In Study 2, we administered four progressively increasing intravenous dexmedetomidine infusions to 16 awake volunteers. In Study 3, we recorded vasomotion simultaneously from 6 fingers of 7 patients who were under dexmedetomidine-based anesthesia. Five-minute epochs of PPG recordings that displayed slow vascular oscillations were analyzed for frequency and amplitude.

Results: In Study 1, vasomotion frequencies were 0.025 ± 0.008 Hz. In Study 2, vasomotion frequencies were 0.033 ± 0.006 Hz, and 0.032 ± 0.008 Hz during the two highest dexmedetomidine infusion steps. In Study 3, vasomotion frequencies ranged from 0.020 to 0.037 Hz and were observed in all 6 fingers, with no synchrony between the six fingers.

Conclusion: The vascular oscillations we observed without significant interference from other spontaneous oscillations are independent of neural activity (Study 1), local in nature (Study 3), and associated with alpha-2-adrenoceptor activation, consistent with known properties of vasomotion.

Introduction: In our study, the possible role of the calcium-sensing receptor (CaSR) pathway in L-cysteine-/hydrogen sulfide (H₂S)-induced vasorelaxations was investigated in isolated mouse thoracic aorta tissue.

Methods: For this purpose, vasorelaxations to L-cysteine (H₂S substrate; 1 µm-10 mm) and calindol (CaSR agonist; 0.3-10 μm) were measured in endothelial-intact and -denuded thoracic aorta segments contracted with phenylephrine (5 μm). Also, the effects of propargylglycine (PAG) and Calhex-231, cystathionine-gamma-lyase (CSE) and CaSR inhibitor, respectively, on L-cysteine- and calindol-induced vasorelaxations were investigated in thoracic aorta segments. In addition, the effects of L-cysteine, calindol, and endothelium on H₂S generation in mouse aorta segments were investigated.

Results: L-cysteine- and calindol-induced vasorelaxations were reduced in the presence of PAG and Calhex-231. Furthermore, in endothelium-denuded tissues, the vasorelaxations to calindol and L-cysteine were reduced compared to endothelium-intact tissues. Also, calindol increased basal H₂S generation, and PAG and Calhex-231 reduced the increase in H₂S production stimulated with calindol. Calhex-231 reduced the increase in H₂S production in the presence of L-cysteine. Also, H₂S production decreased in endothelium-denuded tissues.

Conclusion: Endogenous H₂S generated by CSE produces endothelium-dependent relaxation by activating CaSR in mouse thoracic aorta tissue.

Introduction: Immunosuppressive medications are widely used to treat patients with neoplasms, autoimmune conditions, and solid organ transplants. Prior studies indicate that immunosuppression drugs can cause adverse vascular remodeling. Given the systemic effects of the drugs, elucidating cell-type-specific drug effects has been challenging.

Methods: We utilized induced pluripotent stem cell-derived endothelial cells to investigate the role of widely used immunosuppression drugs on endothelial cell function.

Results: We found that among immunosuppression agents, sirolimus reduced basic endothelial cell functions including cell migration, proliferation, acetylated LDL uptake, mitochondrial respiration, and angiogenic properties, while tacrolimus only reduced nitric oxide release.

Conclusions: This model allows for investigation of differential effect of immunosuppression drugs on endothelial function that can elucidate the mechanisms contributing to clinically observed adverse vascular profiles.

Introduction: Abdominal aortic aneurysm (AAA) is a multifactorial disease with limited identification of contributing genetic factors. p27kip, also known as CDKN1B, is a cell cycle inhibitor that regulates vascular smooth muscle cells (VSMCs) and macrophages (Mϕ). The role of p27 in AAA development was assessed by AAA induction in p27 knockout (p27-/-) and wild-type (WT) mice.

Methods: AAAs were induced in male and female p27-/- and WT mice via topical elastase with oral administration of 3-aminopropionitrile fumarate salt. Aortic diameter was measured with ultrasound. VSMCs and macrophages were quantified by immunohistochemistry. Oxidative stress genes were analyzed using polymerase chain reaction. In vitro cell proliferation, migration, and oxidative stress assay were performed on VSMCs isolated from abdominal aortas.

Results: p27-/- mice developed significantly larger AAA diameter than WT mice with reduced VSMCs and increased macrophages. M1ϕ were significantly elevated in p27-/- mice, while M2ϕ were more abundant in WT mice. p27-/- mice had lower expression of the antioxidant gene, Nrf2. In vitro experiments demonstrated increased proliferation and migration in p27-/- cells with increased oxidative stress sensitivity.

Conclusion: Knockout of p27 accelerated aneurysm growth with increased macrophage infiltration, VSMC loss, and decreased antioxidant factors, highlighting a potential role for p27 in AAA progression.

Introduction: Given the lack of effective pharmacotherapy for vascular dementia (VaD) and the reported benefits of exercise, this study examined the impact of water temperature during aquatic exercise (AE) on cognitive and pathological outcomes in a mouse model of VaD.

Methods: Twelve-month-old male mice underwent bilateral common carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion. Groups included sham, BCAS control (no exercise), and BCAS mice assigned to AE in water baths at 25°C, 30°C, or 35°C. Cognitive performance was assessed using the elevated plus maze, Y-maze, and novel object recognition test (NORT). Brain tissues were analyzed for microglial marker CD68, astrocytic marker GFAP, and myelin basic protein (MBP) in the corpus callosum.

Results: The 30°C AE group showed the greatest improvement in NORT performance and swim activity. CD68 expression was unchanged across groups, but GFAP expression was significantly reduced at 30°C, suggesting suppressed astrocyte activation. Furthermore, the decline in MBP expression after BCAS was attenuated in this group, indicating preserved white matter integrity.

Conclusion: AE at approximately 30°C alleviated cognitive deficits in a VaD model, likely by reducing neuroinflammation and protecting myelin. These findings highlight the therapeutic potential of optimizing AE conditions, particularly water temperature, for dementia-related rehabilitation.

Introduction: Investigation into vascular health and disease across elevated risk conditions has been intensively studied for many years. However, the ability to understand integrated vascular health status has been challenging, as most previous work has focused on specific outcomes, interventions, or potential mechanistic links. While these efforts have revealed many factors contributing to vasculopathy, challenges remain for comparing results across research groups, models, and conditions to understand vascular health status. In the present study, our objective was to quantify sex-dependent differences in peripheral and cerebral vascular health across metabolic disease.

Methods: Utilizing the vascular health index (VHI), a validated metric allowing for simultaneous assessment of vascular reactivity/endothelial function, vascular wall mechanics, and microvessel density within cerebral and skeletal muscle networks, we focus on the impact of elevated metabolic disease risk between male and female obese Zucker rats (OZR). In addition, we study VHI in female OZR following ovariectomy (OVX), with all outcomes compared to results from "healthy" lean Zucker rats (LZRs).

Results: Across all ages, male and female LZR demonstrated comparable VHI, although increased metabolic disease risk reduced both skeletal muscle and cerebral VHI in male OZR more rapidly, and to a greater extent, as compared to female OZR. Protection for VHI for female OZR with elevated disease risk was dependent on intact sex hormone cycling, as OVX in female OZR removed protection in VHI compared to normal female OZR.

Conclusion: These results indicate that sex-based protections in peripheral and cerebral vascular health with metabolic disease in female OZR (versus males) are present at multiple levels of resolution and are dependent on normal female sex hormone cycling.

Introduction: The role of dietary antioxidants in preventing or delaying the progression of cardiovascular-kidney-metabolic (CKM) syndrome remains underexplored. We aimed to develop and interpret a machine learning (ML) model to predict advanced CKM stages based on dietary antioxidant profiles.

Methods: Data were analyzed from 10,257 adults aged >30 years in the NHANES 2007-2010 and 2017-2018 cycles. Dietary antioxidant intake was estimated using two 24-h dietary recalls. Five ML algorithms were trained with rigorous hyperparameter optimization and evaluated comprehensively. SHapley Additive exPlanations (SHAP) was applied to elucidate feature importance and individual-level contributions. An online prediction tool was deployed to enhance clinical utility.

Results: The eXtreme Gradient Boosting (XGBoost) model achieved the highest predictive performance, yielding an area under the curve of 0.901. SHAP analysis identified seven key predictors: age, sex, smoking status, magnesium, zinc, myricetin, and catechin. Older age, male sex, and smoking were associated with increased CKM risk, whereas higher intakes of magnesium, myricetin, zinc, and catechin were protective.

Conclusions: XGBoost effectively predicted advanced CKM stages using a concise set of seven features. Explainable AI approaches such as SHAP enhance model transparency and clinical translation, supporting personalized CKM risk stratification based on dietary antioxidant patterns.

Background: The impairment of vascular smooth muscle cells (VSMCs) causes many vascular diseases, such as atherosclerosis, hypertension, and heart conditions. Research has shown that N6-methyladenosine (m6A) modification regulates VSMCs' function in a vascular environment.

Summary: By regulating RNA metabolism, m6A modification affects key biological processes in VSMCs, such as proliferation, migration, phenotypic transformation, and apoptosis. We aim to examine the role of m6A modification and its associated enzymes in vascular diseases caused by VSMC dysfunction and explore its potential as a therapeutic target so that we can develop drugs targeting VSMC dysfunction on a scientific basis.

Key messages: m6A modification's role in cardiovascular disorders and potential as a therapeutic target demand further study as a critical regulating component in VSMC biology.

Introduction: Unstable human artery plaques can suddenly rupture, leading to MI or stroke. Identification of blood markers associated with unstable plaque features is clearly needed. Humans with symptomatic carotid atherosclerotic plaques have increased infiltration of CD56bright natural killer (NK) cells into the plaque, yet whether subjects with unstable coronary artery plaque features have increased frequencies of circulating CD56bright NK cells is unknown.

Methods: Coronary artery intravascular ultrasound (IVUS) was performed on subjects presenting for medically indicated coronary angiography. Eighteen subjects stratified into high and low percent (%) necrotic core and matched for age, body mass index (BMI), and lipids underwent mass cytometry by time-of-flight analysis on their peripheral blood mononuclear cells collected prior to imaging. Clustering of major immune cell populations was performed on live singlets and CD56 bright and dim NK subsets were quantitated.

Results: Subjects with high necrotic core had a significantly greater frequency of circulating CD56bright NK cells compared to subjects with low necrotic core (p = 0.02). Additionally, the frequency of circulating CD56bright NK cells positively associated with IVUS-VH metrics of total atheroma volume (p = 0.0013), percent (%) atheroma burden (p = 0.0048), % maximum stenosis (p = 0.0021), % necrotic (p = 0.0013), % calcium (p = 0.0016), % fatty (p = 0.0097) and negatively associated with % fibrous (p < 0.0001), an IVUS-VH metric of plaque stability.

Conclusion: These findings suggest that the frequency of CD56bright NK cells may be a safe, noninvasive marker of plaque volume and instability.