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Purpose: Breast cancer affects millions of women worldwide, and for many, therapy results in treatment-induced menopause. Menopausal symptoms in breast cancer survivors are often more severe, frequent, and of greater duration compared with natural menopause. Hot flushes and night sweats pose a significant burden for many women, with limited therapeutic options as menopausal hormone therapy is contraindicated. Guidelines recommend non-hormonal pharmacological agents including clonidine, gabapentin, and some antidepressants. However, some women may be reluctant to use medications due to concerns about side effects. The aim of this narrative review was to appraise recent evidence for nonpharmacological treatments for vasomotor symptoms in breast cancer survivors including cognitive behavioural therapy, hypnosis, yoga, mindfulness, acupuncture, and lifestyle changes., Methods: A literature search was conducted. Studies were included if they were randomised and involved breast cancer survivors and nonpharmacological treatments for menopausal vasomotor symptoms., Results: Twelve studies met the criteria, and three studies of exercise in healthy menopausal women were included. Cognitive behavioural therapy reduces menopausal symptoms and perceived impact of hot flushes and night sweats in breast cancer survivors and is cost effective. The efficacy of hypnosis as a treatment for menopausal vasomotor symptoms in women with breast cancer is supported by two randomised controlled trials. Yoga and acupuncture may reduce vasomotor symptom frequency and/or burden. Studies of exercise as an intervention for vasomotor symptoms in healthy menopausal women have not shown benefit., Conclusion: Evidence for nonpharmacological interventions supports cognitive behavioural therapy and hypnosis in the management of vasomotor symptoms in breast cancer survivors.

Background: A greater frequency of vasomotor symptoms (VMSs) has been associated with higher low-density lipoprotein cholesterol (LDL-C), but the association with high-density lipoprotein cholesterol (HDL-C) remains unclear. Endogenous estradiol (E2) levels are associated with both VMS and lipid levels and thus may confound such associations., Objectives: To assess the relationship of VMS frequency with HDL-C, LDL-C, and lipoprotein concentrations (HDL and LDL particles [HDL-P; LDL-P]) and lipoprotein sizes in midlife women and to evaluate whether these associations are explained by E2., Methods: Participants were from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study who had both nuclear magnetic resonance (NMR) spectroscopy lipoprotein subclass metrics and self-reported frequency of VMS measured 2-5 times over the menopause transition. VMS frequency was categorized into none, 1-5 days (infrequent), or ≥6 days (frequent) within the past 2 weeks., Results: We evaluated 522 women [at baseline: mean age 50.3 (SD: 2.8) years; infrequent VMS: 29.8%, frequent VMS: 16.5%]. Adjusting for potential confounders except E2, frequent VMS was associated with smaller HDL size [β(SE): -0.06 (0.03); P = .04] and higher concentrations of LDL-C [β(SE): 3.58 (1.77); P = .04] and intermediate LDL-P [β(SE): 0.09 (0.05); P = .04] than no VMS. These associations were largely explained by E2, all P's > .05., Conclusions: Frequent VMSs were associated with smaller HDL size and higher concentrations of LDL-C and intermediate LDL-P. These associations were explained by endogenous E2. Whether treating frequent VMS with exogenous E2 could simultaneously improve lipids/lipoproteins profile should be assessed in future studies., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Aim: Although coronary endothelial vasomotor dysfunction predicts future coronary events, there are few human studies showing the relationship between endothelial vasomotor dysfunction and atheroma plaque progression in the same coronary artery. This study examined whether endothelial vasomotor dysfunction is related to atheroma plaque progression in the infarct-related coronary artery of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessment of coronary plaque size with intravascular ultrasound (IVUS) and coronary vasomotor responses to acetylcholine (ACh)., Methods: This study included 50 patients with a first acute STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention (PCI). IVUS and vasomotor response to ACh in the LAD were measured within two weeks of acute myocardial infarction (AMI) (1 st test) and repeated six months (2 nd test) after AMI under optimal anti-atherosclerotic therapies., Results: Percent atheroma volume (PAV) and total atheroma volume (TAV) in the LAD progressed over six months of follow-up in 18 and 14 patients, respectively. PAV and TAV progression was significantly associated with persistent impairment of epicardial coronary artery dilation and coronary blood flow increase in response to ACh at both the 1 st and 2 nd tests. PAV and TAV progression had no significant association with traditional risk factors, PCI-related variables, medications, and the coronary vasomotor responses to sodium nitroprusside, an endothelium-independent vasodilator., Conclusions: Persistent impairment of endothelial vasomotor function in the conduit arterial segment and the resistance arteriole was related to atheromatous plaque progression in the infarct-related coronary arteries of STEMI survivors.

The importance of sharing experimental data in neuroscience grows with the amount and complexity of data acquired and various techniques used to obtain and process these data. However, the majority of experimental data, especially from individual studies of regular-sized laboratories never reach wider research community. A graphical user interface (GUI) engine called Neurovascular Network Explorer 2.0 (NNE 2.0) has been created as a tool for simple and low-cost sharing and exploring of vascular imaging data. NNE 2.0 interacts with a database containing optogenetically-evoked dilation/constriction time-courses of individual vessels measured in mice somatosensory cortex in vivo by 2-photon microscopy. NNE 2.0 enables selection and display of the time-courses based on different criteria (subject, branching order, cortical depth, vessel diameter, arteriolar tree) as well as simple mathematical manipulation (e.g. averaging, peak-normalization) and data export. It supports visualization of the vascular network in 3D and enables localization of the individual functional vessel diameter measurements within vascular trees. NNE 2.0, its source code, and the corresponding database are freely downloadable from UCSD Neurovascular Imaging Laboratory website 1 . The source code can be utilized by the users to explore the associated database or as a template for databasing and sharing their own experimental results provided the appropriate format.

Background: Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs)., Patients and Methods: For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12 months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline., Results: Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2 % of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7 %, respectively. About 80 % of newly occurring symptoms were Grade 1, and less than 5 % were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5 %) during the first year and the mean time to onset was 5.6 months. Patients with vasomotor symptoms were significantly younger (mean 62.8 years, range 38-86 vs 64.7 years, range 37-84; p = 0.02), had higher body mass index (BMI) (23.4 kg/m 2 , range 15.8-39.9 vs 22.4 kg/m 2 , range 15.8-34.9; p = 0.01), had vasomotor symptoms sooner after menopause (12.4 years, range 0-51 vs 15.1 years, range 1-37; p = 0.002), and had more menopausal disorders during menopause (63.3 vs 36.7 %; p = 0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95 % confidence interval (CI) 1.02-1.16; p = 0.009] and experiencing menopausal disorders (OR 2.11, 95 % CI 1.35-3.30; p = 0.001) were significantly associated with vasomotor symptoms., Conclusion: High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

Background: Natural estrogen decline leads to vasomotor symptoms (VMS). Hormone therapy alleviates symptoms but increases cancer risk. Effective treatments against VMS with minimal cancer risks are needed. We investigate the effects of a highly bioavailable aglycone rich Red Clover isoflavone treatment to alleviate existing menopausal VMS, assessed for the first time by 24hour ambulatory skin conductance (SC)., Methods and Results: We conducted a parallel, double blind, randomised control trial of 62 peri-menopausal women aged 40-65, reporting ≥ 5 hot flushes/day and follicle stimulating hormone ≥35 IU/L. Participants received either twice daily treatment with bioavailable RC extract (RCE), providing 34 mg/d isoflavones and probiotics, or masked placebo formulation for 12 weeks. The primary outcome was change in daily hot flush frequency (HFF) from baseline to 12 weeks using 24hr SC. Secondary outcomes were change in SC determined hot flush intensity (HFI), self-reported HFF (rHFF) and hot flush severity (rHFS), blood pressure and plasma lipids. A significant decrease in 24hr HFF (P < 0.01) and HFI (P<0.05) was found when comparing change from baseline to 12 months of the RCE (-4.3 HF/24hr, CI -6.8 to -2.3; -12956 μS s-1, CI -20175 to -5737) with placebo (0.79 HF/24hr, CI -1.56 to 3.15; 515 μS s-1, CI -5465 to 6496). rHFF was also significantly reduced (P <0.05)in the RCE (-2.97 HFs/d, CI -4.77 to -1.17) group compared to placebo (0.036 HFs/d, CI -2.42 to 2.49). Other parameters were non-significant. RCE was well tolerated., Conclusion: Results suggest that moderate doses of RCE were more effective and superior to placebo in reducing physiological and self-reported VMS. Findings support that objective physiological symptom assessment methods should be used together with self-report measures in future studies on menopausal VMS., Trial Registration: ClinicalTrials.gov NCT02028702.

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P<.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension., (© 2015 Wiley Periodicals, Inc.)

Background and Purpose: Emerging work has linked menopausal vasomotor symptoms (VMS) to subclinical cardiovascular disease (CVD) among women. However, VMS are dynamic over time. No studies have considered how temporal patterns of VMS may relate to subclinical CVD. We tested how temporal patterns of VMS assessed over 13 years were related to carotid intima media thickness (IMT) among midlife women., Methods: The Study of Women's Health Across the Nation is a longitudinal cohort study of midlife women. Eight hundred and eleven white, black, Hispanic, and Chinese participants with a well-characterized final menstrual period completed measures of VMS, a blood draw, and physical measures approximately annually for 13 years. Women underwent a carotid artery ultrasound at study visit 12., Results: Four trajectories of VMS were identified by trajectory analysis (consistently high, early-onset, late-onset, persistently low VMS) and tested in relation to carotid indices in linear regression models. Results indicated that women with early-onset VMS had both greater mean IMT (beta, b [standard error, SE]=0.03 [0.01], P=0.03) and greater maximal IMT (b [SE]=0.04 [0.01], P=0.008) than women with consistently low VMS, adjusting for demographics and CVD risk factors., Conclusions: This is the first study to test trajectories of VMS in relation to subclinical CVD. Women with VMS early in the menopause transition had higher mean IMT and maximal IMT than those with consistently low VMS across the transition. Associations were not accounted for by demographic factors nor by CVD risk factors. Results can signal to women in need of early CVD risk reduction., (© 2015 American Heart Association, Inc.)

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.

Objective: The purpose of this study was to determine whether cyclooxygenase inhibition improves vascular dysfunction of adipose microvessels from obese humans., Design and Methods: In 20 obese subjects (age 37 ± 12 years, BMI 47 ± 8 kg/m²), subcutaneous and visceral fat were collected during bariatric surgery and characterized for adipose depot-specific gene expression, endothelial cell phenotype, and microvascular function. Vasomotor function was assessed in response to endothelium-dependent agonists using videomicroscopy of small arterioles from fat., Results: Arterioles from visceral fat exhibited impaired endothelium-dependent, acetylcholine-mediated vasodilation, compared to the subcutaneous depot (P < 0.001). Expression of mRNA transcripts relevant to the cyclooxygenase pathway was upregulated in visceral compared to subcutaneous fat. Pharmacological inhibition of cyclooxygenase with indomethacin improved endothelium-dependent vasodilator function of arterioles from visceral fat by twofold (P = 0.01), whereas indomethacin had no effect in the subcutaneous depot. Indomethacin increased activation via serine-1177 phosphorylation of endothelial nitric oxide synthase in response to acetylcholine in endothelial cells from visceral fat. Inhibition of endothelial nitric oxide synthase with N(ω)-nitro-L-arginine methyl ester abrogated the effects of cyclooxygenase-inhibition suggesting that vascular actions of indomethacin were related to increased nitric oxide bioavailability., Conclusions: Our findings suggest that cyclooxygenase-mediated vasoconstrictor prostanoids partly contribute to endothelial dysfunction of visceral adipose arterioles in human obesity., (Copyright © 2013 The Obesity Society.)

Cardiovascular dysfunction usually occurs after high thoracic and cervical spinal cord injury (SCI). The disruption of supraspinal vasomotor pathways (SVPs) results in the loss of bulbospinal regulation of sympathetic preganglionic neurons, leading to hypotension and compensatory tachycardia at rest. Episodic autonomic dysreflexia can develop upon sensory stimulation below the level of injury. In rodents, the precise spatial distribution of SVPs in the spinal cord originating from the rostral ventrolateral medulla (RVLM) has not been fully defined. To facilitate future studies of axon regeneration to regain cardiovascular control, we injected biotinylated dextran amine (BDA) bilaterally into the RVLM to anterogradely trace SVPs in Fischer 344 (F344) rats. Three weeks later, BDA-labeled descending projections were predominantly localized within the dorsolateral funiculus throughout the cervical and thoracic spinal segments as expected. Additionally, BDA-labeled fibers were also observed in ventral white matter. After a T4 dorsal hemisection to interrupt the dorsolateral funiculus, BDA labeled terminals originating from the ventral white matter as well as serotonergic projections were still detected in regions of autonomic nuclei below the injury. Based on these results, we examined cardiovascular responses after different lesions at spinal level T4, including lateral or dorsal hemisection, dorsolateral or complete transection. Hemodynamic dysfunction and autonomic dysreflexia were only elicited in rats with complete T4 transections when all SVPs were disrupted. Hence, F344 rats with complete T4 transections provide a reliable model for investigating means to improve cardiovascular functional recovery after SCI., (Published by Elsevier B.V.)

We studied the immunolocalization of hemeoxygenase-2 in neurons of the medulla oblongata in men (n=8), aged 18-44 years, who died from causes unrelated to the injury of the central nervous system and in people with the lifetime diagnosis of hypertension (n=6). It has been found that neurons with enzyme positive reaction are present in all parts of the medulla oblongata with concentrations ranging from 0.5 to 13.7% of the total number of cells. The high proportion of small neurons with the high or moderate density of deposits was found in the sensory nuclei. Large cells of the motor nuclei often exhibit the negative or low intensity of the enzymatic reaction. In arterial hypertension, a decrease in the proportion AH NO-positive neurons and the average optical density of the reaction product was noted. The reduction was seen in most affected neurons in the rostral part of the solitary tract nucleus and the lateral reticular nucleus. In the motor nuclei and in the dorsal nucleus of the vagus nerve, these parameters decreased as well although the reduction was not as great as observed in the sensory nuclei.

Vasoprotective effects of erythropoietin in animal models are mediated by endothelium-derived NO and/or mobilization of EPCs (endothelial progenitor cells) and may be enhanced by ischaemia: whether they are present in humans is unknown. We examined whether the erythropoietin analogue darbepoetin improves FMD (flow-mediated dilatation), a measure of endothelium-derived NO, and whether this is influenced by preceding I/R (ischaemia/reperfusion). A total of 36 patients (50-75 years) with stable coronary artery disease were randomized to receive a single dose of darbepoetin (300 μg) or saline placebo. FMD was measured at the brachial artery using high-resolution ultrasound. CD133⁺/CD34⁺/VEGFR2⁺ (vascular endothelial growth factor receptor 2) circulating EPCs were enumerated by flow cytometry. Measurements were made immediately before darbepoetin/placebo and at 24 h, 72 h and 7 days. At 24 h, FMD was repeated after 20 min of I/R of the upper limb. A further group of 11 patients was studied according to the same protocol, all receiving darbepoetin, with omission of forearm I/R at 24 h. Immunoreactive erythropoietin peaked at 24 h and remained elevated at approximately 50-fold of baseline at 72 h. FMD did not differ significantly between groups at 24 h (before I/R). At 72 h (48 h after I/R), FMD was greater (by 2.3±0.5% in the darbepoetin compared with the placebo group, a 66% increase over baseline; P<0.001) and greater than FMD at the same time point without preceding I/R (P<0.01). Increases in CD133⁺/CD34⁺/VEGFR2⁺ cells after darbepoetin did not differ according to the presence or absence of preceding I/R. Preceding I/R is required for darbepoetin to enhance endothelial function, possibly by increasing expression of the erythropoietin receptor and by a mechanism likely to involve Akt/NO rather than circulating EPCs.

This paper is devoted to the analysis of the results of the author's investigations concerning spinal cord injuries. The voluminous material obtained with the use of up-to-date research methods (histological, histochemical, and biochemical) includes basic data on the mechanisms of regulation of blood circulation under normal conditions and in the case of a mechanical injury. It is shown that pathological morphological changes in the affected areas of the spinal cord as well as activities of transport enzymes in the capillaries and the reactive processes in the monoaminoergic nervous apparatus of he arteries may be used as the objective criteria for the determination of the time of the injury. The results of these studies find application in the practical diagnostic work for the estimation of the time of the spinal cord injury.

The development and use of nanoparticles have alerted toxicologists and regulators to issues of safety testing. By analogy with ambient air particles, it can be expected that small doses are associated with a small increase in risk of cardiovascular diseases, possibly through oxidative stress and inflammatory pathways. We have assessed the effect of exposure to particulate matter on progression of atherosclerosis and vasomotor function in humans, animals, and ex vivo experimental systems. The type of particles that have been tested in these systems encompass TiO(2), carbon black, fullerene C(60), single-walled carbon nanotubes, ambient air particles, and diesel exhaust particles. Exposure to ambient air particles is associated with accelerated progression of atherosclerosis and vasomotor dysfunction in both healthy and susceptible animal models and humans at risk of developing cardiovascular diseases. The vasomotor dysfunction includes increased vasoconstriction as well as reduced endothelium-dependent vasodilatation; endothelium-independent vasodilatation is often unaffected indicating mainly endothelial dysfunction. Pulmonary exposure to TiO(2), carbon black, and engineered nanoparticles generate vasomotor dysfunction; the effect size is similar to that generated by combustion-derived particles, although the effect could depend on the exposure period and the administered dose, route, and mode. The relative risk associated with exposure to nanoparticles may be small compared to some traditional risk factors for cardiovascular diseases, but superimposed on these and possible exposure to large parts of the population it is a significant public health concern. Overall, assessment of vasomotor dysfunction and progression of atherosclerosis are promising tools for understanding the effects of particulate matter., (© 2011 Informa Healthcare USA, Inc.)

The distribution of nitroxidergic neurons and activities of neuronal NO synthase in them in some nuclei of the bulbar vasomotor center were studied in patients with early forms of arterial hypertension. Activity of neuronal NO synthase is reduced significantly in the majority of nuclei in patients with early forms of arterial hypertension, while the content of NO-positive cells was only slightly changed. More pronounced changes in this parameter were detected in the solitary tract nuclei in comparison with the reticular formation nuclei, which had efferent relationships with the intermediate lateral spinal nucleus.

Structure of the efferent nerve plexuses (adrenergic, acetylcholinestherase- and cholinacetyltranspherase-positive, NO-dependent), was studied in the arteries of human leptomeninx with different diameters. Material was obtained from the corpses of the healthy people and of the patients with initial stages of arterial hypertension (AH). It was shown that the concentrations of cholinergic and adrenergic nerve fibers and varicosities in axon terminal part, innervating the arteries with the diameters ranging from 450 till 100 microm, were not significantly different. In these arteries, NO-ergic plexuses were also detected. In patients with AH, regardless the arterial diameters, the significant increase (up to 15-20%) of adrenergic nerve fiber and varicosity concentrations was found. The changes in cholinergic nerve fiber concentration were found to depend on the vessel diameter: the significant decrease of these parameter was observed only in arteries with the diameter of 100-200 microm. No significant changes in nerve plexus concentration was noticed in the arteries with greater or smaller diameter. In NO-ergic neural conductors, the enzyme activity decreased only in the large arteries, and remained almost unchanged in the small vascular branches. The changes in the vasomotor innervation described in AH, are interpreted as a vasomotor innervation dysfunction of the leptomeninx arteries that may result in the hemodynamic disturbances.

Activation of the estrogen receptor-alpha (ERalpha) mediates the vasculoprotective effects of estrogen, in part, through modulating nitric oxide (NO) production and vasodilation. Whereas inflammation is accompanied by altered vascular reactivity and underlies the pathogenesis of vascular disease, the role of the ERalpha in the vascular responses associated with acute systemic inflammation remains poorly characterized. Contractile and relaxation responses of isolated aortic segments were investigated 12 h after ip injection of saline or lipopolysaccharide (LPS, 10 mg/kg) in male wild-type (ERalpha(+/+)) and ERalpha-deficient (ERalpha(-/-)) mice. As previously observed, LPS-injected ERalpha(+/+) mice displayed reduced contractile responses to phenylephrine and enhanced vasodilation in response to acetylcholine. In contrast, aortic tissues from LPS-injected ERalpha(-/-) mice displayed enhanced contractile responses and reduced sensitivity to acetylcholine- and sodium nitroprusside-induced vasodilation. LPS treatment in ERalpha(+/+) and ERalpha(-/-) mice resulted in similar increased levels of systemic NO production and inducible NO synthase expression in the vascular wall. However, expression of mRNA and protein for endothelial NOS and soluble guanylate cyclase (alpha- and beta-subunits) were significantly reduced in aortic tissues from LPS-treated ERalpha(-/-) animals, possibly accounting for reduced endothelial NO production and reduced smooth muscle responses to NO. These findings represent new evidence of the functional role of ERalpha in the male vasculature and suggest that during acute LPS-induced inflammatory responses, the ERalpha mediates the sustained expression of the molecular machinery essential for endothelial NO synthesis (i.e. endothelial NOS) and the vascular responses to NO (i.e. soluble guanylate cyclase).

Background: Central hypoventilation and paroxysmal hypertension are uncommon complications of medullary infarction. To our knowledge, the combination of these autonomic complications of medullary stroke has not previously been reported., Objective: To describe a patient who experienced life-threatening paroxysmal attacks of central apnea and vasomotor instability 3 months after medullary infarction, a combination of symptoms that is unusual. PATIENT, METHODS, AND RESULTS: Following a right lateral medullary infarction, an otherwise stable 70-year-old woman developed recurrent episodes of apnea (PCO2), > 100 mm Hg), blood pressure instability (systolic blood pressure, > 200 to < 100 mm Hg), and mental status changes (from agitation to coma) within hours of removal from mechanical ventilation. These attacks occurred repeatedly after removal from mechanical ventilation and were prevented by diaphragm pacing with a phrenic nerve pacemaker and nocturnal mechanical ventilation via a tracheostomy., Conclusions: A syndrome of life-threatening central hypoventilation and vasomotor instability can occur after medullary infarction. Placement of a phrenic nerve pacemaker can prevent these complications, without the functional limitations imposed by continuous mechanical ventilation.

In humans with cardiovascular risk factors, increased vascular production of superoxide anion may contribute to endothelial dysfunction by its reacting with nitric oxide and reducing its biological activity. High concentrations of ascorbic acid scavenge superoxide anion and restore normal endothelium-dependent vasodilation in humans with cardiovascular risk factors. To investigate the contribution of increased superoxide anion to endothelial dysfunction in atherosclerotic coronary arteries, we examined the effect of sequential infusions of ascorbic acid (final concentration 0.1, 1.0, and 10 mmol/L) or placebo on coronary endothelial function in 26 subjects referred for cardiac catheterization to evaluate coronary artery disease. Coronary vasomotor function was evaluated using intracoronary agonist infusion, quantitative angiography, and intracoronary Doppler measurements. At baseline, endothelium-dependent vasodilation of epicardial arteries and coronary microvessels was impaired to an equivalent extent in the ascorbic acid and placebo groups. Sequential ascorbic acid infusions had no effect on the acetylcholine-induced change in coronary artery diameter (-11+/-8, -12+/-10, and -9+/-9%) compared with the effect of placebo (-14+/-13, -16+/-10, and -13+/-9%) infusions (p=0.98). Similarly, the changes in coronary blood flow during acetylcholine infusions were equivalent during ascorbic acid (51+/-44, 67+/-66, and 62+/-52%) and placebo (61+/-104, 55+/-93, and 50+/-69%) infusions (p=0.63). Ascorbic acid also had no effect on the dilator response to intracoronary nitroglycerin (p=0.19). These data argue against an important role for superoxide-mediated "inactivation" of nitric oxide or another rapidly reversible form of oxidative stress as a mechanism of coronary endothelial dysfunction in patients with coronary atherosclerosis.

Cardiovascular dysfunction is common after cervical spinal cord injury (SCI) in humans. At least three spinal cord elements involved in cardiovascular control have been identified: descending vasomotor pathways (DVPs), sympathetic preganglionic neurons, and spinal afferents. However, little is known about the localization of the DVPs within the human spinal cord, which limits our understanding of the mechanisms of cardiovascular dysfunction after SCI. This study was undertaken to examine the association of cardiovascular abnormalities after SCI in humans with the severity of degeneration and axonal loss within the DVPs. A detailed chart review and histopathological examination of postmortem spinal cord tissue was conducted in individuals with cervical SCI (n = 7) and control individuals with an intact central nervous system (n = 5). Individuals with SCI were divided into group 1 (severe cardiovascular abnormalities) and group 2 (no/minor cardiovascular disturbances). The area of degeneration and the number of preserved axons within different areas of the spinal cord were quantitated using EMPIX imaging software. Two areas of possible localization of DVPs were investigated: area I, within the dorsal aspects of the lateral funiculus; and area II, within the white matter adjacent to the dorsolateral aspect of the lateral horn. Comparison of the extent of axonal degeneration in both SCI groups demonstrated that individuals in group 1 had more extensive axonal degeneration than those in group 2. The number of intact axons within areas I and II in individuals from group 1 was significantly lower than those from group 2 or control cases (p = 0.029; p = 0.028). The most dramatic axonal loss was observed within area I in individuals with cardiovascular dysfunction. We conclude that loss and degeneration of DVPs, which are localized within the dorsolateral aspects of the human spinal cord, contributes to abnormal cardiovascular control after SCI. This information adds to our knowledge of pathobiology of cardiovascular dysfunction after human SCI and may ultimately suggest novel therapeutic strategies as regenerative and reparative approaches become translated to the clinic.

Placement of an ameroid constrictor in large-conduit pig coronary arteries causes progressive stenosis and distal myocardial ischemia. Blood perfusion in the ischemic region is partly dependent on vasomotor responses to neural and humoral factors distal to the occlusion site. To ascertain the degree of impairment of vascular function in pigs, the authors induced myocardial ischemia by placing an ameroid constrictor in the left circumflex coronary artery and examined vascular reactivity and histopathology distal to the constriction site. The sensitivity of the distal left circumflex coronary and nonoccluded control left anterior descending arteries to PGF(2alpha) was similar. After nitric oxide blockade using Nw-nitro-l-arginine methylester (l-NAME), the sensitivity and maximal contraction to PGF(2alpha) were significantly increased in both the left circumflex coronary (EC50: 5.86 +/- 0.74 vs. 3.28 +/- 0.84 microM; C(max): 4.63 +/- 0.28 vs. 6.25 +/- 0.30 g, P < 0.01) and left anterior descending (EC50: 6.57 +/- 0.73 vs. 2.78 +/- 0.16 microM; C(max): 5.09 +/- 0.37 vs. 6.95 +/- 0.39 g, P < 0.01) arteries. Substance P-induced relaxation (100 pM) was blocked to a larger degree in the distal left circumflex coronary artery when compared with the left anterior descending artery (76.9 +/- 4.2% vs. 56.4 +/- 3.1%, P < 0.05). Endothelium-independent relaxation to sodium nitroprusside was similar in the left circumflex coronary and left anterior descending arteries before and after nitric oxide blockade. Histopathologic examination showed no major differences between distal left circumflex coronary artery segments and left anterior descending artery controls. However, scanning electron microscopy showed endothelial hypertrophy and activation in specimens from the left circumflex coronary arteries. In summary, as a result of the major hemodynamic changes induced by a chronic constriction and eventual occlusion of a large coronary artery, distal segments underwent adaptive compensatory changes. Such compensation may be related to an increased nitric oxide production by the hypertrophic endothelium in response to alterations in coronary hemodynamics.

Vasomotor reactivity is decreased in terms of cerebral blood flow (CBF) response to hypercapnia in patients with cerebrovascular white matter (WM) lesions. This study evaluated whether vasomotor reactivity is altered during postural change in these patients. We examined 28 consecutive patients with cerebrovascular WM lesions, subgrouped into 19 with Schmidt scale 2 and 9 with scale 3 WM lesions. These patients were compared with 15 age-matched patients with lacunar infarction but without significant WM lesions and 6 controls without cerebrovascular disease. With blood pressure monitoring, brain SPECT scans were done in the supine and upright position using HMPAO as a tracer. The ratio of radioisotope (RI) counts in the frontal and parieto-temporal lobes to those in the cerebellar hemispheres (CBF ratio) was evaluated. In the comparison among the three groups, there were no significant differences in the changes of systemic blood pressure after rising. The baseline CBF ratio in the supine position was also not different among the three groups. After rising, the CBF ratio in each region of interest (ROI) did not change significantly in either lacunar infarction or control groups. By contrast, in patients with WM lesions, the CBF ratio in the frontal lobe decreased after rising (p < 0.0001). In the subgroup analysis, there was a significant increase in blood pressure 1, 2 and 3 min after rising (p < 0.05), with a higher tendency in the scale 3 WM lesion group as compared to the scale 2 WM lesion group. The CBF ratio was decreased in both frontal and parieto-temporal areas in the scale 2 WM lesion group, whereas this was significant only in the frontal areas in the scale 3 WM lesion group. Vasomotor reactivity is impaired in cerebrovascular WM lesions, suggesting a susceptibility to postural changes in these patients.

Purpose: To assess the effects of endovascular irradiation on vascular structure and function in pig coronary arteries in the absence of vascular injury., Methods and Materials: Vasomotor responses to contractions of KCl and prostaglandin F2alpha (PGF2alpha), relaxations to endothelium-dependent (substance P, A23187) and -independent (sodium nitroprusside, SNP) agents; endothelial morphology and superoxide anion (02*-) production were investigated in control (naive), sham and irradiated (20 Gy, 32P) arteries 1 month after irradiation., Results: Contractions to KCl and PGF2alpha in the presence of L-NAME were significantly decreased, relaxations to substance P and A23187 were abolished and SNP-induced relaxation was potentiated in irradiated arteries compared to naive and sham-treated vessels. Scanning electron microscopy (SEM) revealed enlarged endothelial cells (ECs) exhibiting surface microvilli. O2*- production was significantly increased in irradiated vessels (437.0 +/- 37.3 vs. 126.0 +/- 11.6 RLU/s/mg tissue, P < .01)., Conclusions: One month after brachytherapy, normal pig coronary arteries showed abnormal vascular reactivity, altered endothelial morphology and increased production of O2*-. Lack of relaxation to substance P and A23187 reflects ionizing radiation-mediated damage to ECs, whereas potentiation of relaxation to SNP suggests additional deleterious effects on medial smooth muscle cells (SMCs). Increased O2*- production might have contributed to endothelial dysfunction by scavenging nitric oxide (NO).

FUNCTIONS OF THE ENDOTHELIUM: The endothelium plays a pivotal role in regulating vasomotor tone, vessel permeability, blood cell extravasation, and antiatherogenic, antithrombogenic and antiadhesive processes., Dysfunction of the Endothelium: Demonstrated, in particular, by endothelium-dependent vasomotricity disorders, endothelium dysfunction occurs in many psysiological and pathological situations that lead to atherosclerosis: advanced age, menopause, high blood pressure, dyslipidemia, diabetes, smoking, elevated homocysteinemia, chronic renal failure.... These dysfunctions of the endothelium constitute the fundamental and very early step in the development of atherosclerosis., Prevention: Specific treatment of functional anomalies of the endothelium can be an essential element in the prevention of atherosclerosis. In certain cases, he cause of endothelial dysfunction may be related to the presence of radical oxygen species, nitric oxide inhibitors, or increased synthesis or release of endothelin. Potential treatments should be adapted to the specific cause of the underlying endothelial anomaly: antioxidants, statins, anti-endothelins, or converting enzyme inhibitors. In clinical practice, it may be important to recognize the cause of endothelial dysfunction for adapted early drug therapy.

Objective: To investigate the effects of intestinal ischemia and reperfusion (I/R) on the pulmonary vascular endothelium and smooth muscle., Summary Background Data: Respiratory failure is an important cause of death and complications after intestinal I/R. Although the mechanism of respiratory failure in this setting is complex and poorly understood, recent studies of lung injury suggest that endothelial dysfunction may play a significant role., Methods: A rat model of acute lung injury was studied after 60 minutes of superior mesenteric arterial occlusion followed by either 120 or 240 minutes of reperfusion. The pulmonary vasomotor function was examined in isolated lungs perfused at a constant flow rate., Results: Sixty minutes of intestinal ischemia followed by 120 or 240 minutes of reperfusion led to a significant reduction in the ability of the pulmonary vasculature to respond to angiotensin II, acetylcholine, and calcium ionophore but not to nitroglycerin. The vasoconstriction response to N(G)-nitro-L-arginine methyl ester, which is a measure of basal nitric oxide release, was diminished in the 240-minute reperfusion group. Intestinal I/R was also associated with pulmonary leukosequestration and increased pulmonary microvascular leakage., Conclusions: Basal and agonist-stimulated release of nitric oxide from the pulmonary vascular endothelium and the ability of pulmonary smooth muscle to contract in response to angiotensin II were impaired by intestinal I/R. Such functional impairment in both pulmonary vascular endothelium and smooth muscle may contribute to the alveolocapillary dysfunction and pulmonary hypertension found in acute lung injury after intestinal I/R.

Background: A model of shunt-induced pulmonary hypertension was used to study the effects of pulmonary overcirculation on endothelial nitric oxide synthase (eNOS) and cytochrome P450-4A (cP450-4A) vasodilatory mechanisms and related hemodynamic responses., Methods: An aortopulmonary shunt was constructed in 6-week-old piglets (n = 7, sham-operated controls n = 8). Hemodynamic measurements were made 4 weeks later under serial experimental conditions: baseline (fractional concentration of oxygen, 0.4); inhaled nitric oxide, 25 ppm (INO); hypoxia (fractional concentration of oxygen, 0.14); hypoxia + INO; N(omega)-nitro-L-arginine methylester (L-NAME 30 mg/kg intravenously, competitive NOS inhibitor); and L-NAME + INO. Lung protein levels of eNOS and cP450-4A and NOS activity were compared between groups., Results: Shunted animals had a higher baseline pulmonary artery pressure (p < 0.05). L-NAME resulted in a greater increase in pulmonary vascular resistance in shunted animals (150% +/- 26% shunt versus 69% +/- 14% control; p = 0.01). The INO administered during baseline conditions decreased pulmonary vascular resistance only in control animals (p < 0.05). Protein levels of eNOS and NOS activity were similar in both groups; however, cP450-4A protein levels were decreased in the shunted group (p = 0.02)., Conclusions: The NO production was preserved in shunted animals but they demonstrated greater vasodilatory dependence on NO, evidenced by an exaggerated increase in pulmonary vascular resistance after NOS inhibition. Loss of the cP450-4A vasodilatory system may be the driving force for NO dependency in the shunted pulmonary circulation.

Background: The distribution of neural structures in human nasal vasculature is still not completely understood. To date, immunocytochemical and histochemical studies of the innervation pattern and neurotransmitter distribution have only been performed using light microscopy. The aim of this study was to verify these results by electron microscopy and to obtain new knowledge of the innervation of the individual vessel types. The target was to determine the role of the different vessels in the swelling mechanism in human nasal mucosa., Material and Methods: Specimens were prefixed in glutaraldehyde and postfixed in osmium tetroxide. After dehydration they were embedded in araldite. Ultrathin sections were cut, contrasted with uranylacetate and lead citrate, and studied under EM., Results: Nasal vasculature is controlled by a dense innervation. Amyelinated longitudinal nerve bundles and smaller axon conglomerates are detected in the arterial adventitia. Capacitance vessels (veins) in general show few nerve structures, which, in contrast to arteries, are also located between the smooth muscle cells. Cushion veins, however, reveal a stronger innervation pattern especially in their muscular swelling. In contrast to smaller arterioles, no axons can de demonstrated in capillaries., Conclusion: The density of innervation in arteries and cushion veins seems to indicate that these vessel types are the central neural control point for the swelling mechanism in human nasal mucosa. Capillary function, however, does not seem to be directly influenced by the autonomic nervous system.

Purpose: To examine the anterior optic nerve vasomotor effects of nonselective and relatively beta-1-selective beta-adrenergic antagonists in rabbits, because different influences on optic nerve blood flow with these medications have been suggested., Methods: After topical therapy for 30 days with either timolol maleate 0.5% (six rabbits), betaxolol hydrochloride 0.5% (six rabbits), or placebo (two rabbits), the microvasculature of the optic nerve was examined with an intraluminal microvascular corrosion casting technique. The investigators were masked to both the medication group and the treated eye. The constriction, in percent of the downstream vessel caliber, was measured at the vascular branching point of arterioles supplying the anterior optic nerve. An average constriction was calculated and compared between the medication groups and between the treated and the contralateral, untreated eyes., Results: Constriction values from a total of 218 arterioles supplying the anterior optic nerve were obtained for the 14 rabbits. The means of the average constriction on the treated side were comparable between the groups treated with timolol maleate, betaxolol hydrochloride, and placebo (one-way analysis of variance, P = .64), as well as between the treated and untreated eyes (two-tailed t-test for paired variables, P = .68 for timolol maleate and P = .42 for betaxolol hydrochloride). The statistical power to find a difference of 5% or more average constriction was at least 90%., Conclusions: Both relatively selective and nonselective beta-adrenergic antagonists produce no observable optic nerve vasomotor effects in the rabbit eye.

INTRODUCTION--Cerebral blood vessels are innervated by sympathetic nerve fibres storing neuropeptide Y (NPY), parasympathetic nerves storing acetylcholine, vasoactive intestinal peptide (VIP) and sensory afferent fibres containing calcitonin gene-related peptide (CGRP), substance P (SP) and neurokinin A. In experimental studies on subarachnoid haemorrhage (SAH) there are indications that perivascular peptides are involved. In the present study we have in man measured the levels of NPY, VIP, SP and CGRP in brain vessels of patients that have suffered a fatal SAH and compared this with the levels encountered in subjects that died of an extracerebral cause. MATERIAL AND METHODS--Vessels from patients who have died from SAH or nonSAH were obtained during autopsy performed within 24 hrs after death. The peptides were extracted and fractionated with reversed phase liquid chromatography (HPLC). The levels of NPY, VIP, SP, and CGRP were measured with radioimmunoassay. Vasomotor responses of human cerebral arteries were performed using a sensitive in vitro system. RESULTS--Human cerebral vessels contained NPY, VIP, CGRP and SP which eluted at the same positions as the authentic peptides. The level of CGRP was significantly lower (p < 0.01) in arteries removed from SAH patients as compared to control subjects. The level of SP was not changed, if anything it tended to be increased after SAH. The levels of NPY and VIP were not significantly altered after SAH. In isolated brain vessels alpha-CGRP was a potent vasodilator of arteries precontracted with whole blood, prostaglandin F2 alpha or endothelin. It had a poor effect on vessels precontracted with 60 mM potassium. CONCLUSION--The evidence suggest that the trigemino-cerebrovascular system, storing CGRP and SP, is to a differential degree involved in the pathophysiology of SAH in man and supports the hypothesis of an exhaustion of CGRP as one important factor in the development of late spasm occurring after SAH.