Vascular Smooth Muscle Dysfunction Research Articles

Relationship of cumulative low-density lipoprotein cholesterol with atherosclerosis

Abstract Background The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. Objective The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). Methods This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg･year/dL, 4000-4999 mg･year/dL, 5000-5999 mg･year/dL, and ≥6000 mg･year/dL. Results The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg･year/dL group was significantly higher than the odds ratios in the other groups (Figure 1A). The odds ratio of the lower quartile of NID in the <4000 mg・year/dL group was significantly higher than the odds ratios in the 5000-5999 mg･year/dL and ≥6000 mg･year/dL groups (Figure 1B). The odds ratio of the prevalence of CCA plaque in the <4000 mg・year/dL group was significantly higher than that in the ≥6000 mg･year/dL group (Figure 1C). Conclusions Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg・year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg･year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg･year/dL.Graphical abstractFigure 1

Relationship between peripheral and intracoronary blood flow in patients with angina and nonobstructive coronary arteries.

Coronary vasomotor dysfunction, an important underlying cause of angina and nonobstructive coronary arteries (ANOCA), encompassing coronary vasospasm, coronary endothelial dysfunction, and/or coronary microvascular dysfunction, is clinically assessed by invasive coronary function testing (ICFT). As ICFT imposes a high burden on patients and carries risks, developing noninvasive alternatives is important. We evaluated whether coronary vasomotor dysfunction is a component of systemic microvascular endothelial and smooth muscle dysfunction and can be detected using laser speckle contrast analysis (LASCA). Forty-three consecutive patients with ANOCA underwent ICFT, with intracoronary acetylcholine, adenosine, and flow measurements, to assess coronary vasomotor dysfunction. Cutaneous microvascular function was assessed using LASCA in the forearm, combined with vasodilators acetylcholine, sodium nitroprusside, and insulin and using EndoPAT, by measuring the reactive hyperemia index (RHI). Of the 43 included patients with ANOCA (79% women, 59 ± 9 yr old), 38 patients had coronary vasomotor dysfunction, including 28 with coronary vasospasm, 26 with coronary endothelial dysfunction, and 18 with coronary microvascular dysfunction, with overlapping endotypes. Patients with and without coronary vasomotor dysfunction had similar peripheral flow responses to acetylcholine, insulin, and RHI. In contrast, coronary vasomotor dysfunction was associated with lower peripheral flow responses to sodium nitroprusside (P < 0.001). An absolute flow response to sodium nitroprusside of 83.95 APU resulted in 86.1% sensitivity and 80.0% specificity for coronary vasomotor dysfunction (area under the ROC curve, 0.883; P = 0.006). In conclusion, this study provides evidence of systemic vascular smooth muscle dysfunction in patients with ANOCA with coronary vasomotor dysfunction and the diagnostic value of peripheral microvascular function testing as a noninvasive tool for detecting coronary vasomotor dysfunction.NEW & NOTEWORTHY This study provides proof of concept that assessment of the peripheral vasculature, particularly vascular smooth muscle cells measured using the LASCA technology holds potential as a noninvasive tool for detecting coronary vasomotor dysfunction. This finding highlights the potential of the LASCA technology in, for example, medication studies for coronary vasomotor dysfunction, especially when investigating whether medication improves vascular function, as repeated peripheral measurements are less invasive than invasive coronary function testing, the current gold standard.

Sex Differences and Role of Lysyl Oxidase Like 2 (LOXL2) in Angiotensin II-Induced Hypertension in Mice.

Hypertension, a disease with known sexual dimorphism, accelerates aging associated arterial stiffening, in part due to the activation of matrix remodeling caused by increased biomechanical load. In this study, we tested the effect of biological sex and the role of the matrix remodeling enzyme lysyl oxidase like 2 (LOXL2) in hypertension induced arterial stiffening. Angiotensin II (Ang II) was delivered using osmotic pumps in Loxl2+/- and WT male and female mice. Blood pressure and pulse wave velocity (PWV) were measured noninvasively to assess hypertension and aortic stiffness. Wire myography and uniaxial tensile testing were used to test aortic vasoreactivity and mechanical properties. Aortic wall composition was examined by histology and Western blotting. The effect of biomechanical strain on LOXL2 expression and secretion by vascular smooth muscle (VSMC) and endothelial cells (EC) was evaluated by uniaxial cyclic stretching of cultured cells. The role of LOXL2 catalytic function on VSMC alignment in response to mechanical loading was determined with LOXL2 inhibition and knockout. Ang II infusion induced hypertension in WT and Loxl2+/- mice of both sexes and increased PWV in WT males but not in Loxl2+/- males, WT females, or Loxl2+/- females. LOXL2 depletion protected males from Ang II mediated potentiation of vasoconstriction but worsened in females and improved aortic mechanical properties in both sexes. Histological analysis showed increased aortic wall thickness in hypertensive WT males but not females and increased intralamellar distance in both sexes, that was ameliorated in Loxl2+/- mice. Western blotting revealed increased collagen I, decreased collagen IV, and increased LOXL2 accumulation and processing in hypertensive mice. Hypertensive cyclic strain contributed to LOXL2 upregulation in the cell-derived matrix in VSMCs but not ECs. LOXL2 catalytic function facilitated VSMC alignment in response to biomechanical strain. In males, arterial stiffening in hypertension is driven both by VSMC response and matrix remodeling. Females exhibit a delayed onset of Ang II-induced hypertension with minimal ECM remodeling but with VSMC dysfunction. LOXL2 depletion ameliorates arterial stiffening and preserves functional contractility and aortic structure in male hypertensive mice. LOXL2 depletion improves aortic mechanics but worsens aortic contractility in hypertensive females. VSMCs are the primary source of LOXL2 in the aorta and hypertension increases LOXL2 processing and shifts to collagen I accumulation. Overall, LOXL2 depletion offers protection in young hypertensive males and females.

The role of cardiac PET in diagnosis and prognosis of patients with ischemia with no obstructive coronary arteries (INOCA)

Chest pain, a common symptom in cardiovascular care, often leads to the investigation of obstructive coronary artery disease (CAD). However, many patients experience chest pain without obstructive CAD, termed INOCA (Ischemia with Non-Obstructive Coronary Arteries) or CMD (Coronary Microvascular Dysfunction). INOCA can be attributed to endothelial dysfunction, vascular smooth muscle dysfunction, or both, affecting about 20–30 % of patients with nonobstructive CAD. The diagnostic approach for INOCA includes both invasive and non-invasive methods, with cardiac PET (Positron Emission Tomography) playing a significant role in risk stratification and management. PET evaluates various parameters like myocardial blood flow under stress and rest, myocardial flow reserve, and myocardial ischemia. Such comprehensive assessment is essential in accurately diagnosing and managing INOCA, considering the complexity of this condition.

Menopause: An Early Obesogenic Condition Associated with Vascular Smooth Muscle Dysfunction

Background: For several years menopause was considered a natural event faced by women entering their 40’s. Evidence has now recognized that menopause causes a series of metabolic and vascular complications that negatively affect women later in life. Approximately, 65% of American menopausal women become overweight or obese which increases their risk of developing vascular events, such as hypertension. However, the mechanisms by which menopause leads to weight gain and vascular complications remain understudied. By using a preclinical model of menopause, our preliminary data shows that menopausal mice exhibit early weight gain and development of metabolic disorders. Therefore, we hypothesize that menopause causes an early onset of obesity and metabolic disorders that may precede the development of vascular complications. Methods: To address our hypothesis, eight-week-old female C57BL/6 mice were randomized into two experimental groups: Control/Sham Group (n=9) and Ovariectomized (OVX) group (n=8). The OVX group had their ovaries surgically removed and the Sham Group underwent surgery, but the ovaries were not removed. Metabolic parameters, including glucose metabolism and metabolic cages, and body weight were analyzed along the 20 weeks of the experimental protocol. At the terminal experiments, thoracic aortas were isolated and mounted in a wire myograph for vascular reactivity studies. Phenylephrine (PE) concentration response curves were utilized to assess vascular smooth muscle functionality. Results: After one week following the surgery, the OVX group showed a significant increase in body weight (19.4 ± 0.37g vs. 18.2 ± 0.40g controls, p&lt;0.05), however, obesity was only confirmed in week 16 with the BMI (0.26 ± 0.003 vs. 0.24 ± 0.003 controls, p&lt;0.05) and abdominal circumference (8.4 ± 0.14cm vs. 8.05 ± 0.06cm controls, p&lt;0.05). Intriguingly, OVX group exhibited reduced food consumption (2.26 ± 0.11g vs. 3.36 ± 0.21g controls, p&lt;0.05) water intake (3.11 ± 0.54 mL vs. 4.48 ± 0.18mL controls, p&lt;0.05), fecal output (1.14 ± 0.07g vs. 2.10 ± 0.21g controls, p&lt;0.05) and water intake (3.11 ± 0.54mL vs. 4.48 ± 0.18mL controls, p&lt;0.05). Regarding glucose metabolism, the OVX group exhibited increased fasting glucose (125.4 ± 8.03mg/dL vs. 86.7 ± 2.67mg/dL controls, p&lt;0.05), glucose intolerance (AUC: 39086.88 ± 2201.01 vs. 22939.56 ± 3187.55 controls, p&lt;0.05), and increased triglycerides (116.0 ± 26.11mg/dL vs. 37.3 ± 4.23mg/dL controls, p&lt;0.05). Vascular studies revealed a significant vascular smooth muscle dysfunction in the OVX group as evidenced by reduced aortic contractility to phenylephrine (EMax: 8.15 ± 1.1mN vs.12.3 ± 1.53mN controls, p&lt;0.05). Conclusion: Our results reveals that menopause causes an early onset of weight gain that is not related to increased consumption of food but instead to an decreased metabolism. Menopausal mice developed central obesity, high fasting glucose, and high triglycerides, which taken together characterize metabolic syndrome that was accompanied by vascular smooth muscle dysfunction. NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Serum Fibroblast Growth Factor 23 Levels are Associated with Vascular Smooth Muscle Dysfunction in Type 2 Diabetes.

Increased level of serum fibroblast growth factor 23 (FGF23) is a hallmark of abnormal phosphate metabolism in patients with chronic kidney disease (CKD) and is recently shown to be associated with the risk of cardiovascular disease even in those without CKD. This study investigated the association between serum FGF23 levels and vascular function in patients with type 2 diabetes. This was a cross-sectional study involving 283 Japanese patients with type 2 diabetes. Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) of the brachial artery were measured via ultrasonography to evaluate vascular endothelial and smooth muscle functions, respectively. Serum intact FGF23 levels were determined via a sandwich enzyme-linked immunosorbent assay. The median values of FMD, NMD, and serum FGF23 were 6.0%, 14.0%, and 27.3 pg/mL, respectively. The serum FGF23 levels were inversely associated with NMD but not with FMD, and the association was independent of atherosclerotic risk factors, estimated glomerular filtration rate (eGFR), and serum phosphate levels. Furthermore, the relationship between serum FGF23 levels and NMD was modified by kidney function, which was pronounced in subjects with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2). Serum FGF23 levels are independently and inversely associated with NMD in patients with type 2 diabetes, particularly in those with normal kidney function. Our results indicate that FGF23 is involved in vascular smooth muscle dysfunction and that increased serum levels of FGF23 may serve as a novel biomarker for vascular smooth muscle dysfunction in patients with type 2 diabetes.

Association of cumulative low-density lipoprotein cholesterol exposure with vascular function

The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).

Effects of concurrent aerobic and resistance training on vascular health in type 2 diabetes: a systematic review and meta-analysis.

To determine the impacts of concurrent aerobic and resistance training on vascular structure (IMT) and function (PWV, FMD, NMD) in type 2 diabetes (T2D). The electronic databases PubMed, Web of Science Core Collection, Cochrane Library, Embase, Scopus, CINAHL, and SPORTDiscus were systematically searched for articles on "type 2 diabetes" and "concurrent training" published from inception to August 2, 2022. We included randomized controlled trials that examined the effects of concurrent training versus passive controls on IMT, PWV, FMD and NMD in T2D. Ten studies were eligible, including a total of 361 participants. For IMT, concurrent training showed a slight decrease by 0.05mm (95% CI -0.11 to 0.01, p > 0.05). concurrent training induced an overall significant improvement in FMD by 1.47% (95% CI 0.15 to 2.79, p < 0.05) and PWV by 0.66m/s (95% CI -0.89 to -0.43, p < 0.01) in type 2 diabetics. However, concurrent training seemed to exaggerate the impaired NMD (WMD = -2.30%, 95% CI -4.02 to -0.58, p < 0.05). Concurrent training is an effective method to improve endothelial function and artery stiffness in T2D. However, within 24 weeks concurrent training exacerbates vascular smooth muscle dysfunction. More research is needed to explore whether longer and/or higher-intensity concurrent training interventions could enhance the vascular structure and smooth muscle function in this population. www.crd.york.ac.uk/PROSPERO/, identifier CRD42022350604.

Chronic Unpredictable Stress Impairs Vascular Reactivity in Male and Female Mice

Background: Chronic stress is known to induce vascular inflammation causing endothelial and vascular smooth muscle dysfunction. Changes in the hypothalamic-pituitary-adrenal axis lead to increased sympathetic and decreased parasympathetic drive, causing the release of inflammatory cytokines in the vasculature, by mechanisms that are unclear. Hypothesis: We hypothesize that chronic unpredictable stress (CUS) increases reactive oxygen species and induces gasdermin pore formation and voltage-dependent anion channel (VDAC) oligomerization in the membrane of the mitochondria, which releases mitochondrial DNA (mtDNA) to the cytosol and induces TNF-α, IL-1β and IL-18 production through activation of the NLRP-3 inflammasome pathway. Methods: Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of chronic unpredictable stress (CUS) or handling (CTL). Systolic blood pressure (SBP) was measured at the end of the stress period by tail cuff plethysmography. Vascular function using myographs was assessed on isolated mesenteric resistance arteries (MRAs), pudendal artery (PA) and aorta from male and female CUS and CTL mice. The arterial rings were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2. Concentration-response curves to phenylephrine (PE; 1nM-30μM) and acetylcholine (ACh; 1nM-30μM) were performed. Expression of gasderminD was measured in the MRA by western blot. Concentration-response curves were analyzed using non-linear regression analysis. Data are presented as mean ± S.E.M. Statistical significance set at p&lt;0.05. Data were analyzed with GraphPad Prism 9.2.0. Results: SBP was increased by 12.1±4.9% in CUS mice. In CUS mice, compared to the CTL, the potency of ACh-induced relaxation was decreased in the MRA (pEC50 CUS 6.17±0.09 vs CTL 6.81±0.11; p=0.003) and PA (pEC50 CUS 6.65±0.07 vs CTL 6.31±0.09; p=0.008) but not in the aorta of male mice. In females, the potency to ACh was decreased only in the MRA (pEC50 CUS 5.94±0.30 vs CTL 6.98±0.15; p=0.041). There were no differences in the contractile responses to PE between controls and mice exposed to CUS in the MRA and PA of both males and females, while in the aorta of CUS males, there was a significant reduction in maximal response (EMAX CTL: 4.70±0.48 mN vs CUS 3.01± 0.23mN; p=0.007). The expression of gasderminD was increased in MRA of female mice only. Conclusion: Our results show that, in both sexes, CUS increased SBP and induced vascular dysfunction observed by impaired reactivity to ACh and PE, with increased expression of gasderminD in MRA of female mice only. These results suggest that the vascular adaptations to CUS are sex-dependent. This work was supported by NIH grants P20GM109091 (F.H.), R01HL130972-01A1 (F.G.S.), R01HL5949 (F.G.S.), RO1DK132948 (C.W. &amp; F.P.) and R01 MH129798 (SKW); VA grants: VISN7 RDA (F.H.), Merit awards: BX000168-10A1 (F.G.S.), BX005320 (F.G.S.), and BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vasospastic angina in women: Clinical backgrounds and prognoses of patients younger than and older than 60 years

We frequently encounter cases of women with vasospastic angina (VSA). Additionally, some women with VSA are younger than 60 years old. However, it is unknown whether the characteristics of VSA in women aged < 60 years are different from those in women aged ≥ 60 years. To investigate and compare the clinical characteristics and prognosis of VSA in women aged < 60 years from those in women aged ≥ 60 years. We enrolled 94 women with VSA who were diagnosed using the spasm provocation test. According to the age at diagnosis, the patients were divided into two groups: Group Y (age < 60 years, n = 17) and Group O (age ≥ 60 years, n = 77). Flow-mediated dilation (FMD) and nitroglycerin (NTG)-induced dilation (NID) of the brachial artery were performed and assessed using brachial ultrasonography. Moreover, conventional coronary risk factors, such as atherosclerotic lesions (stenosis > 20%) detected using coronary angiography and focal spasms (coronary spasm within one segment of one coronary artery), and major cardiovascular adverse events (MACE) were assessed in both groups. Smoking was more prevalent in Group Y than in Group O (P = 0.04). FMD was similar in both groups (Group O: 4.3% ± 3.2%, Group Y: 4.5% ± 3.3%; P = 0.75), whereas NID was higher in Group Y (20.5% ± 8.6%) than in Group O (13.6% ± 5.3%, P < 0.01). Atherosclerosis was not detected in Group Y but was detected in Group O (61%, P < 0.01). Focal spasms were less frequent in Group Y (12%) than in Group O (38%, P = 0.04). The incidence of major adverse cardiac events did not differ between the two groups (P = 0.40). Women aged < 60 years with VSA have less atherosclerotic lesions and focal spasms. These characteristics may be affected by smoking habits and vascular smooth muscle dysfunction.

Critical role of the coronary microvasculature in heart disease: From pathologic driving force to “innocent” bystander

The coronary microvasculature is responsible for providing oxygen and nutrients to myocardial tissue. A healthy microvasculature with an intact and properly functioning endothelium accomplishes this by seemless changes in vascular tone to match supply and demand. Perturbations in the normal physiology of the microvasculature, including endothelial and/or vascular smooth muscle dysfunction, result in impaired function (vasoconstriction, antithrombotic, etc.) and structural (hypertrophic, fibrotic) abnormalities that lead to microvascular ischemia and potential organ damage. While coronary microvascular dysfunction (CMD) is the primary pathologic driving force in ischemia with non-obstructive coronary artery disease (INOCA), angina with no obstructive coronary arteries (ANOCA), and myocardial infarction with non-obstructed coronary arteries (MINOCA), it may be a bystander in many cardiac disorders which later become pathologically associated with signs and/or symptoms of myocardial ischemia. Importantly, regardless of the primary or secondary basis of CMD in the heart, it is associated with important increases in morbidity and mortality. In this review we discuss salient features pertaining to known pathophysiologic mechanisms driving CMD, the spectrum of heart diseases where it places a critical role, invasive and non-invasive diagnostic testing, management strategies, and the gaps in knowledge where future research efforts are needed.

Retinal Vascular Disease in Limb-Girdle Muscular Dystrophy.

To report bilateral retinal vascular occlusive disease in limb-girdle muscular dystrophy. Case report. A 34-year-old Asian woman was referred for evaluation and management of central retinal vein occlusion. Ultra-wide-field fluorescein angiography showed resolving initial peripheral retinal vein occlusion in one eye and peripheral venular segmental staining in the fellow asymmetric eye. Genetic testing established the diagnosis of limb-girdle muscular dystrophy (LGMD). Similar to other forms of muscular dystrophy, LGMD is caused by genetic abnormalities in sarcolemma proteins, a key structural component that connects the intracellular cytoskeleton of a myofiber to the extracellular matrix. Like other muscular dystrophies, LGMD may be associated with retinal vascular abnormalities noted. In this case, retinal vascular smooth muscle dysfunction was seen in LGMD, analogous to reported vascular abnormalities in other muscular dystrophies such as facioscapulohumeral dystrophy and Duchenne muscular dystrophy.

Influenza A virus elicits peri-vascular adipose tissue inflammation and vascular dysfunction of the aorta in pregnant mice.

Influenza A virus (IAV) infection during pregnancy initiates significant aortic endothelial and vascular smooth muscle dysfunction, with inflammation and T cell activation, but the details of the mechanism are yet to be clearly defined. Here we demonstrate that IAV disseminates preferentially into the perivascular adipose tissue (PVAT) of the aorta in mice. IAV mRNA levels in the PVAT increased at 1–3 days post infection (d.p.i) with the levels being ~4–8 fold higher compared with the vessel wall. IAV infection also increased Ly6Clow patrolling monocytes and Ly6Chigh pro-inflammatory monocytes in the vessel wall at 3 d.p.i., which was then followed by a greater homing of these monocytes into the PVAT at 6 d.p.i. The vascular immune phenotype was characteristic of a “vascular storm”- like response, with increases in neutrophils, pro-inflammatory cytokines and oxidative stress markers in the PVAT and arterial wall, which was associated with an impairment in endothelium-dependent relaxation to acetylcholine. IAV also triggered a PVAT compartmentalised elevation in CD4+ and CD8+ activated T cells. In conclusion, the PVAT of the aorta is a niche that supports IAV dissemination and a site for perpetuating a profound innate inflammatory and adaptive T cell response. The manifestation of this inflammatory response in the PVAT following IAV infection may be central to the genesis of cardiovascular complications arising during pregnancy.

Relationship of Daily Coffee Intake with Vascular Function in Patients with Hypertension.

We evaluated the relationship of daily coffee intake with endothelial function assessed by flow-mediated vasodilation and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation in patients with hypertension. A total of 462 patients with hypertension were enrolled in this cross-sectional study. First, we divided the subjects into two groups based on information on daily coffee intake: no coffee group and coffee group. The median coffee intake was two cups per day in the coffee group. There were significant differences in both flow-mediated vasodilation (2.6 ± 2.8% in the no coffee group vs. 3.3 ± 2.9% in the coffee group, p = 0.04) and nitroglycerine-induced vasodilation (9.6 ± 5.5% in the no coffee group vs. 11.3 ± 5.4% in the coffee group, p = 0.02) between the two groups. After adjustment for confounding factors, the odds ratio for endothelial dysfunction (OR: 0.55, 95% CI: 0.32–0.95) and the odds ratio for vascular smooth muscle dysfunction (OR: 0.50, 95% CI: 0.28–0.89) were significantly lower in the coffee group than in the no coffee group. Next, we assessed the relationship of the amount of daily coffee intake with vascular function. Cubic spline curves revealed that patients with hypertension who drank half a cup to 2.5 cups of coffee per day had lower odds ratios for endothelial dysfunction assessed by flow-mediated vasodilation and vascular smooth muscle dysfunction assessed by nitroglycerine-induced vasodilation. Appropriate daily coffee intake might have beneficial effects on endothelial function and vascular smooth muscle function in patients with hypertension.

Experimental Preeclampsia Causes Long-Lasting Hippocampal Vascular Dysfunction and Memory Impairment.

Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with memory impairment, cognitive decline and brain atrophy later in life in women at ages as young as early-to-mid 40 s. PE increases the risk of vascular dementia three-fold, however, long-lasting effects of PE on the vasculature of vulnerable brain regions involved in memory and cognition, such as the hippocampus, remain unknown. Here, we used a rat model of experimental PE (ePE) induced by maintaining rats on a 2% cholesterol diet beginning on day 7 of gestation to investigate hippocampal function later in life. Hippocampal-dependent memory and hippocampal arteriole (HA) function were determined in Sprague Dawley rats 5 months after either a healthy pregnancy or ePE (n = 8/group). Rats that had ePE were hypertensive and had impaired vasoreactivity of HAs to mediators involved in matching neuronal activity with local blood flow (i.e., neurovascular coupling). ePE rats also had impaired long-term memory, but not spatial memory. Thus, this model of ePE mimics some of the long-lasting cardiovascular and cognitive consequences that occur in women who previously had PE. These findings suggest endothelial and vascular smooth muscle dysfunction of HAs were present months after PE that could impair hippocampal neurovascular coupling. This represents a novel vascular mechanism by which PE causes early-onset dementia.

Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

BackgroundAdvanced type 2 diabetes mellitus (T2DM) accelerates vascular smooth muscle cell (VSMC) dysfunction which contributes to the development of vasculopathy, associated with the highest degree of morbidity of T2DM. Lysine acetylation, a post-translational modification (PTM), has been associated with metabolic diseases and its complications. Whether levels of global lysine acetylation are altered in vasculature from advanced T2DM remains undetermined. We hypothesized that VSMC undergoes dysregulation in advanced T2DM which is associated with vascular hyperacetylation.MethodsAged male Goto Kakizaki (GK) rats, a non-obese murine model of T2DM, and age-matched male Wistar rats (control group) were used in this study. Thoracic aortas were isolated and examined for measurement of global levels of lysine acetylation, and vascular reactivity studies were conducted using a wire myograph. Direct arterial blood pressure was assessed by carotid catheterization. Cultured human VSMCs were used to investigate whether lysine acetylation participates in high glucose-induced reactive oxygen species (ROS), a crucial factor triggering diabetic vascular dysfunction.ResultsThe GK rats exhibited marked glucose intolerance as well as insulin resistance. Cardiovascular complications in GK rats were confirmed by elevated arterial blood pressure and reduced VSMC-dependent vasorelaxation. These complications were correlated with high levels of vascular global lysine acetylation. Human VSMC cultures incubated under high glucose conditions displayed elevated ROS levels and increased global lysine acetylation. Inhibition of hyperacetylation by garcinol, a lysine acetyltransferase and p300/CBP association factor (PCAF) inhibitor, reduced high glucose-induced ROS production in VSMC.ConclusionThis study provides evidence that vascular hyperacetylation is associated with VSMC dysfunction in advanced T2DM. Understanding lysine acetylation regulation in blood vessels from diabetics may provide insight into the mechanisms of diabetic vascular dysfunction, and opportunities for novel therapeutic approaches to treat diabetic vascular complications.

The Role of Vasospasm and Microcirculatory Dysfunction in Fluoropyrimidine-Induced Ischemic Heart Disease

Cardiovascular diseases and cancer are the leading cause of morbidity and mortality globally. Cardiotoxicity from chemotherapeutic agents results in substantial morbidity and mortality in cancer survivors and patients with active cancer. Cardiotoxicity induced by 5-fluorouracil (5-FU) has been well established, yet its incidence, mechanisms, and manifestation remain poorly defined. Ischemia secondary to coronary artery vasospasm is thought to be the most frequent cardiotoxic effect of 5-FU. The available evidence of 5-FU-induced epicardial coronary artery spasm and coronary microvascular dysfunction suggests that endothelial dysfunction or primary vascular smooth muscle dysfunction (an endothelial-independent mechanism) are the possible contributing factors to this form of cardiotoxicity. In patients with 5-FU-related coronary artery vasospasm, termination of chemotherapy and administration of nitrates or calcium channel blockers may improve ischemic symptoms. However, there are variable results after administration of nitrates or calcium channel blockers in patients treated with 5-FU presumed to have myocardial ischemia, suggesting mechanisms other than impaired vasodilatory response. Clinicians should investigate whether chest pain and ECG changes can reasonably be attributed to 5-FU-induced cardiotoxicity. More prospective data and clinical randomized trials are required to understand and mitigate potentially adverse outcomes from 5-FU-induced cardiotoxicity.

Metabolic Syndrome and Erectile Dysfunction

Metabolic syndrome (MetS) is considered a risk factor for erectile dysfunction (ED), and ED is almost three times more prevalent in men with MetS. Vascular pathologies are a significant factor for the development of ED, and many experts suggest endothelial dysfunction (EnD) as a likely explanation for the association between ED and MetS. Studies also show that corporal vascular and trabecular smooth muscle dysfunction leads ultimately to corporal veno-occlusive dysfunction. Different functional system abnormalities, such as nervous degenerations, hormonal insufficiencies, and metabolic factors (e.g., hyperlipidemia, advanced glycation end products), are also likely involved in the pathophysiological pathways. Autonomic neuropathy is also commonly encountered in patients and animal models of MetS. From another perspective, low testosterone levels may be predictive of MetS. Several studies concluded that components of MetS, such as high blood pressure, obesity, hyperinsulinemia, T2DM, hyperglycemia, hypertriglyceridemia, elevated C-Reactive protein, and low HDL levels, were all associated with decreased serum testosterone levels. Lifestyle modification, such as exercise and diet, are the first-line treatment for MetS. Studies have found that a 10% weight loss has been shown to significantly increase IIEF-5 scores. Exercise was also shown to increase endothelial-derived NO and decrease oxidative stress, resulting in a lower risk of developing ED in physically active men. Metformin combined with PDE5 inhibitors is a promising treatment approach, although with limited research.

Potential Benefits of Flavonoids on the Progression of Atherosclerosis by Their Effect on Vascular Smooth Muscle Excitability.

Flavonoids are a group of secondary metabolites derived from plant-based foods, and they offer many health benefits in different stages of several diseases. This review will focus on their effects on ion channels expressed in vascular smooth muscle during atherosclerosis. Since ion channels can be regulated by redox potential, it is expected that during the onset of oxidative stress-related diseases, ion channels present changes in their conductive activity, impacting the progression of the disease. A typical oxidative stress-related condition is atherosclerosis, which involves the dysfunction of vascular smooth muscle. We aim to present the state of the art on how redox potential affects vascular smooth muscle ion channel function and summarize if the benefits observed in this disease by using flavonoids involve restoring the ion channel activity.

The area under curve for time-course analysis parameters is associated with abdominal aortic aneurysms and the severity of peripheral artery disease in men

BackgroundAbdominal aortic aneurysm (AAA) and peripheral artery disease (PAD) are associated with vascular endothelial dysfunction. To date, flow-mediated vasodilatation (FMD) and nitroglycerin-mediated vasodilatation (NMD) have been used to evaluate vascular function. Recently, parameters of time-course analysis have been proposed as useful evaluations for arteriosclerotic diseases. In this study, the correlation between the parameters of time-course analysis, to the degree of vascular endothelial damage in AAA and PAD, together with their applicability as a vascular function test, was investigated. MethodsBrachial artery vasoreactivity was assessed in male patients with AAA (n = 150) and PAD (n = 50). The percentage change in peak diameters (ΔFMD and ΔNMD), the time to diameter change, the time to peak diameter from the diameter change, the blood flow decay time constant, the area under the curve (AUC), the maximum dilation rate and the extended time constant were measured. ResultsAmong the groups of aneurysm diameter in AAA, the FMD-AUC was highly different (p = .01), while the ΔFMD was not significantly different (p = .36). Among the Fontaine stages in PAD, the FMD-AUC was inversely associated with severity (p = .01) although the ΔFMD was not significantly different (p = .71). Among the Fontaine stages, the NMD-AUC was also inversely associated with severity (p = .03) although the ΔNMD was not significantly different (p = .11). ConclusionThis study suggests that FMD-AUC and NMD-AUC are useful for estimating vascular endothelial and vascular smooth muscle dysfunction, serving as supplementary markers for the diagnosis and evaluation of PAD and AAA.