Systemic Vascular Function Research Articles

Smooth Muscle PPARgamma Mutation Causes Impaired Renal Blood Flow and Salt‐Sensitive Hypertension

Failure to vasodilate the systemic and renal vasculature in response to salt loading is a hallmark of salt sensitive hypertension (HT). Human subjects carrying dominant negative mutations in PPARgamma (PPARG) exhibit early onset HT while global PPARG activation consistently lowers blood pressure (BP). To determine whether tissue‐specific actions of PPARG regulate systemic and renal vascular function, salt sensitivity and BP, we studied mice specifically expressing a human HT‐causing mutation in PPARG P467L in smooth muscle (S‐P467L). S‐P467L transgenic mice and non‐transgenic controls (NT) were fed regular diet (0.4% salt) or high salt (HS) diet containing 4% salt for 4 weeks. Salt induced marked elevations in systolic BP in S‐P467L mice (135 ± 2 mmHg HS vs 121 ± 4 mmHg regular diet), but not in NT mice (121 ± 5 mmHg HS vs 118 ± 3 mmHg regular diet). S‐P467L and NT animals exhibited identical cardiac output at baseline and under chronic HS; thus the pressor effect of salt intake in S‐P467L mice was not due to a larger fluid volume, but likely higher peripheral vascular resistance. In keeping with this, HS‐consuming S‐P467L mice, but not NT controls, exhibited severe impairment in acetylcholine‐ and sodium nitroprusside‐induced vasorelaxation in carotid artery (Maximal relaxation at 30 μM acetylcholine: S‐P467L 35 ± 4% vs. NT 90 ± 2%), basilar artery (S‐P467L −3 ± 9% vs. NT 70 ± 5%), and first order renal arteries branches (S‐P467L 34 ± 4% vs. NT 76 ± 4%). Importantly, salt‐induced vascular dysfunction rapidly developed in S‐P467L mice after receiving HS diet for only 3 days, preceding the BP elevation. In line with the impaired renovascular relaxation, S‐P467L mice failed to adapt their renal blood flow (RBF) to HS (HS‐induced increases in RBF: S‐P467L 3 μL/min/g vs. NT 20 μL/min/g). The impaired renovascular dilation and blunted RBF was not caused by differences in circulating renin‐angiotensin levels or renal sympathetic nerve activity between the two strains. In the 3rd week of HS diet, S‐P467L mice produced 31% less nitrate/nitrite in 24 hour urine compared to NT controls, which was indicative of blunted renal bioavailability of nitric oxide, a potent inhibitor of Na‐K‐2Cl cotransporter (NKCC2). These changes were associated with a declined capacity of HS‐fed S‐P467L mice to excrete excess sodium and volume challenge, which was rescued by an NKCC2 inhibitor furosemide, but not by the Na‐Cl‐cotransporter inhibitor thiazide. Further supporting a role of NKCC2, a single dose of furosemide (20 mg/kg) induced a larger decrease in systolic BP in salt‐consuming S‐P467L mice (S‐P467L HS −16 ± 3 mmHg, S‐P467L regular diet −5 ± 2 mmHg, NT HS −6 ± 2 mmHg, and NT regular diet −6 ± 2 mmHg), while thiazide did not. Our data support the novel concept that smooth muscle PPARG regulates systemic and renal vascular resistance, renal perfusion and tubular sodium transport, and loss of these protective actions of PPARG predisposes to salt sensitivity and hypertension.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal Resistive Index Predicts Post-Bariatric Surgery Renal Outcome in Nondiabetic Individuals with Severe Obesity.

Bariatric surgery may ameliorate renal function through vascular mechanisms. This study tested surgery's ability to improve measured glomerular filtration rate (mGFR) and identified clinical, renal, and systemic vascular predictors of such improvement. Twenty-five nondiabetic subjects with severe obesity were studied before and 1 year after Roux-en-Y gastric bypass, evaluating mGFR and renal plasma flow, basal renal resistive index (RI) and dynamic renal RI, renal visceral fat, and systemic vascular parameters, including flow-mediated dilation, aortic pulse wave velocity, and carotid intima media thickness and stiffness. After Roux-en-Y gastric bypass, BMI decreased by 31%. At follow-up, body surface area (BSA)-adjusted mGFR increased (from 86.9±15.2 to 109.0±18.2 mL/min/1.73 m2 , P< 0.001), whereas the absolute mGFR did not change. Renal plasma flow did not vary. RI decreased; flow-mediated dilation, pulse wave velocity, carotid intima media thickness, and carotid stiffness improved. mGFR changes after surgery (ΔmGFR/BSA) were associated with younger age and lower fasting glucose. Among vascular variables, an improved ΔmGFR/BSA was associated with smaller brachial artery diameter, lower intima media thickness, and lower RI; this latter association remained after adjusting for covariates. No measure of adiposity was associated with ΔmGFR. In subjects with obesity and normal renal function, bariatric surgery improves mGFR/BSA (although absolute mGFR is unchanged) and renal and systemic vascular function. Lower renal intravascular resistance can predict these improvements, maximizing them in relatively young individuals.

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.

Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3−/− mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.

Impact of Nitric Oxide Bioavailability on the Progressive Cerebral and Peripheral Circulatory Impairments During Aging and Alzheimer's Disease.

Advanced aging, vascular dysfunction, and nitric oxide (NO) bioavailability are recognized risk factors for Alzheimer's disease (AD). However, the contribution of AD, per se, to this putative pathophysiological mechanism is still unclear. To better answer this point, we quantified cortical perfusion with arterial spin labeling (PVC-CBF), measured ultrasound internal carotid (ICA), and femoral (FA) artery blood flow in a group of patients with similar age (~78 years) but different cognitive impairment (i.e., mild cognitive impairment MCI, mild AD-AD1, moderate AD-AD2, and severe AD-AD3) and compared them to young and healthy old (aged-matched) controls. NO-metabolites and passive leg-movement (PLM) induced hyperemia were used to assess systemic vascular function. Ninety-eight individuals were recruited for this study. PVC-CBF, ICA, and FA blood flow were markedly (range of 9–17%) and significantly (all p < 0.05) reduced across the spectrum from YG to OLD, MCI, AD1, AD2, AD3 subjects. Similarly, plasma level of nitrates and the values of PLM were significantly reduced (range of 8–26%; p < 0.05) among the six groups. Significant correlations were retrieved between plasma nitrates, PLM and PVC-CBF, CA, and FA blood flow. This integrative and comprehensive approach to vascular changes in aging and AD showed progressive changes in NO bioavailability and cortical, extracranial, and peripheral circulation in patients with AD and suggested that they are directly associated with AD and not to aging. Moreover, these results suggest that AD-related impairments of circulation are progressive and not confined to the brain. The link between cardiovascular and the central nervous systems degenerative processes in patients at different severity of AD is likely related to the depletion of NO.

Menstrual phase and the vascular response to acute resistance exercise

Aerobic exercise has a favorable effect on systemic vascular function, reducing both central (large elastic artery) and peripheral (smaller muscular artery) stiffness. The effects of resistance exercise (RE) on arterial stiffness are more complex. Acute RE increases central artery stiffness while decreasing peripheral stiffness. To date, the majority of studies have been performed in predominantly male participants. To examine the effect of acute RE on central and peripheral arterial stiffnesses in women, a secondary purpose was to explore the influence of cyclic changes in estrogen status across the menstrual cycle on the arterial response to acute RE. 18 healthy women [28 ± 7years, body mass index (BMI) 22.6 ± 2.9kg/m2] completed an acute RE bout during the early follicular and the early luteal phase of their menstrual cycle. Salivary 17β-Estradiol concentration was measured during each phase, using a passive drool technique. Pulse-wave velocity (PWV) was obtained from the carotid-femoral and carotid-radial pulse sites to measure central and peripheral stiffness, respectively, using applanation tonometry. PWV was measured at rest, immediately, 10, 20, and 30min post-RE. 17β-Estradiol concentration was significantly lower in the early follicular vs. the early luteal phase of the menstrual cycle (1.78 ± 0.51 vs. 2.40 ± 0.26pg/ml, p = 0.01). Central PWV significantly increased (p < 0.05) and peripheral PWV significantly decreased (p < 0.05) post-RE in both the early follicular and early luteal phases. No phase-by-time interaction was detected for either vascular segment (p > 0.05). Women experience increases in central arterial stiffness and reductions in peripheral arterial stiffness following acute RE. Menstrual cycle phase may not influence changes in arterial stiffness in response to acute RE.

Nutrients for neurocognition in health and disease: measures, methodologies and mechanisms.

Effective pharmaceutical treatments for age-related cognitive decline have proved elusive. There is, however, compelling evidence that nutritional status and supplementation could play crucial roles in modifying the expression of cognitive change through the lifespan. Subjective memory impairment and mild cognitive impairment can be harbingers of dementia but this is by no means inevitable. Neurocognitive change is influenced by a variety of processes, many of which are involved in other aspects of systemic health, including cardiovascular function. Importantly, many of these processes are governed by mechanisms which may be modified by specific classes of bioactive nutrients. There is increasing, converging evidence from controlled trials that nutritional interventions can improve mood and cognitive function in both clinical and healthy populations. Specific examples include selected botanical extracts such as the flavonoids. Some nutritional supplements (e.g. broad-spectrum micronutrient supplementation) appear to support improved cognitive function, possibly through redressing insufficient nutrient status (i.e. suboptimal but above the threshold for frank deficiency). Recent mechanistic research has unveiled physiologically plausible, modifiable, cognition-relevant targets for nutrition and nutraceuticals. These include processes involved in both systemic and central vascular function, inflammation, metabolism, central activation, improved neural efficiency and angiogenesis. The advent and development of human neuroimaging methodology have greatly aided our understanding of the core central mechanisms of cognitive change. Different imaging modalities can provide insights into modifiable central mechanisms which may be targeted by bioactive nutrients. The latter may contribute to slowing age-related decline through supporting neurocognitive scaffolding mechanisms.

Post-prandial hyperlipidaemia results in systemic nitrosative stress and impaired cerebrovascular function in the aged.

Post-prandial hyperlipidaemia (PPH) acutely impairs systemic vascular endothelial function, potentially attributable to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability (oxidative-nitrosative stress). However, it remains to be determined whether this extends to the cerebrovasculature. To examine this, 38 (19 young (≤35 years) and 19 aged (≥60 years)) healthy males were recruited. Cerebrovascular function (middle cerebral artery velocity, MCAv) and cerebrovascular reactivity to hypercapnea (CVRCO2Hyper) and hypocapnea (CVRCO2Hypo) were determined via trans-cranial Doppler ultrasound and capnography. Venous blood samples were obtained for the assessment of triglycerides (photometry), glucose (photometry), insulin (radioimmunoassay), ascorbate free radical (A•-, electron paramagnetic resonance spectroscopy) and nitrite (NO2-, ozone-based chemiluminescence) in the fasted state prior to and 4 h following consumption of a standardized high-fat meal (1362 kcal; 130 g of fat). Circulating triglycerides, glucose and insulin increased in both groups following the high-fat meal (P<0.05), with triglycerides increasing by 1.37 ± 1.09 mmol/l in the young and 1.54 ± 1.00 mmol/l in the aged (P<0.05). This resulted in an increased systemic formation of free radicals in the young (P<0.05) but not the aged (P>0.05) and corresponding reduction in NO2- in both groups (P<0.05). While the meal had no effect on MCAv in either age group, CVRCO2Hyper was selectively impaired in the aged (P<0.05). These findings indicate that PPH causes acute cerebrovascular dysfunction in the aged subsequent to systemic nitrosative stress.

Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study

BackgroundSodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms.MethodsNeuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used.ResultsDapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p < 0.05), and pulse-wave-velocity was reduced (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < 0.05), even after correction for mean BP. Renal resistive index was reduced (0.62 ± 0.04 to 0.59 ± 0.05, p < 0.05). These vascular modifications were not observed in hydrochlorothiazide-treated individuals.ConclusionsAn acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction.

Relationship between serum inflammatory markers and vascular function in a cohort of adolescents with type 1 diabetes

ObjectiveThe contribution of inflammation to endothelial/vascular dysfunction in early Type I Diabetes (T1D) is not well understood. The objective of this study was to examine the interaction between systemic inflammation and vascular function in adolescent’s with and without-T1D. Methods51 subjects from our observational cohort of adolescents with T1D (JDRF-CCTN), and 59 healthy controls (HC) were studied. Serum cytokines-chemokines were quantified using Human 41-Plex Array, and vascular function was measured by Flow Mediated Dilatation (FMD), Pulse Wave Velocity (PWV) and Blood Pressure (BP). Factor Analysis was used to identify pro- and anti-inflammatory cytokine-chemokine factors, which were then correlated with vascular outcomes. ResultsThree pro-inflammatory factors were identified in HC and three in TID, and a single anti-inflammatory factor in both groups. In HC there was a positive correlation (r=0.33; p=0.01) between control proinflammatory Factor 1 and systolic BP and a negative correlation between control proinflammatory Factor 3(r=−0.29; p=0.02) and diastolic BP. Control proinflammatory Factor 2 correlated positively with PWV. In TID subjects, no correlations were found between any of the pro-inflammatory factors and the vascular measurements. No correlations were found between the anti-inflammatory factors and BP, FMD and PWV in either HC or T1D. Levels of pro-inflammatory analytes, EGF, GRO, PDGF-BB, PDGF-AA and sCD40L were significantly higher in T1D. ConclusionsThe cytokine-chemokine signature in early T1D, prior to the development of arterial disease, is significantly different from that seen in healthy controls. This may be relevant to pathophysiology, determining risk and identifying target cytokines-chemokines for intervention in T1D.

Vascular Function And Progression Of Alzheimer’s Disease

PURPOSE: In aging, cerebral and systemic vascular functions (VF) decline likewise to cognitive decline. Also, reduced availability of nitric oxide (NO) in both cerebral and peripheral blood vessels results in further alterations of VF. So, changes in VF and NO availability may contribute to the development of Alzheimer’s disease (AD). However, current literature lacks of evidence about the progression of AD and VF. To verify if VF is significantly reduced in AD patients compared with age-matched healthy counterparts and if VF declines further with the severity of AD. Potential correlation between VF and NO availability was also assessed. METHODS: In 55 AD patients (severity of dementia distribution: 12 MCI, 15 AD1, 19 AD2, 9 AD3), 13 healthy elderly (OLD), and 10 young (YG) subjects systemic vascular function was assessed by means of passive limb movement (PLM). NO availability was determined via plasma NO metabolites (NO-3+NO-2). RESULTS: Δpeak PLM was 739±150 ml/min, 284±46 ml/min, 227±39, 182±37 ml/min, 166±22 ml/min, 155±26 ml/min in YG, OLD, MCI, AD1, AD2, and AD3 respectively. NO-3+NO-2 was 53±9 μM, 47±3 μM, 42±2 μM, 40±3 μM, 38±3 μM, 35±1 μM in YG, OLD, MCI, AD1, AD2, and AD3 respectively. Correlation between Δpeak PLM and NO-3+NO-2 was r=0.9765. CONCLUSION: Our results confirm that VF is reduced in aging. AD patients exhibited a further reduction of VF compared with healthy age-matched counterparts. Moreover, VF and NO availability were progressively declined with the progression of dementia, implicating that AD and its progression might be the result of an intertwined decline of both neural and vascular functions, likely related to the NO availability.

Sex differences in the inflammatory response and inflammation-induced vascular dysfunction

BackgroundPremenopausal women have a lower incidence of cardiovascular disease, although the exact mechanism underlying this protection is unclear. Both systemic and localised inflammation have a crucial role in the progression of cardiovascular disease, and much preclinical and observational data in human beings suggest that differences in inflammation between the sexes exist. We investigated whether inflammation, and which components of the inflammatory response, might be altered in women compared with men. MethodsWe performed two clinical studies with 24 and 32 healthy volunteers. In 12 men and 12 women (mean age 26·0 years [SD 5·7] and 24·7 [6·8], respectively), we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD) determined with ultrasound. Responses were assessed before administration of typhoid vaccine and then at 8 h and 32 h afterwards. In another study, in 16 male and 16 female volunteers (mean age 27·4 years [SD 1·1] and 26·8 [1·1], respectively), inflammatory exudate and cellular recruitment were measured at 24 h (acute) and 72 h (resolution) in skin blisters induced with cantharidin. Ethics approval was given by NRES: City Road and Hampstead Ethics Committee (11/LO/2038) for both studies. Both studies are registered with ClinicalTrials.gov, number NCT01582321. FindingsTyphoid vaccine caused a mild systemic inflammation, which was associated with a trend to decreased FMD in men and an increased response in women compared with baseline (p=0·006). By 24 h cantharidin induced a fluid-filled blister of a similar volume in both sexes; however, after 72 h blisters had resolved only in women (p=0·003). At 24 h there was a significant reduction in both monocyte (p=0·003) and lymphocyte count (p=0·011) in blisters in women compared with those in men. A generalised reduction in the activation state of all major leucocytes including neutrophils was evident in women. These differences in cell recruitment and activation were associated with higher proresolving mediators, including the D-resolvins, and a reduction in concentrations of the neutrophil chemoattractant leukotriene B4. InterpretationOur findings suggest that female sex protects against endothelial dysfunction induced by systemic inflammation. This effect is probably due to a rapid resolution of inflammation in women specifically targeting the neutrophil through elevation of the D-resolvin pathway. FundingKR receives doctoral research fellowship funding from the National Institute for Health Research. JD receives funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement 677542), and is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z).

Systemic oxidoreductive balance and vascular function in individuals without clinical manifestation of atherosclerosis.

IntroductionEndothelial dysfunction is recognized as the earliest disorder in the development of atherosclerosis, in the pathogenesis of which oxidative stress plays a crucial role. The aim of this study was to determine the relationships between non-invasive parameters of vascular dysfunction and oxidative stress.Material and methodsForty-eight individuals without clinical manifestation of atherosclerosis were studied. The plasma concentrations of the following were determined in all 48 subjects: retinol, ascorbic acid, α-tocopherol and uric acid, as well as the products of oxidative DNA damage repair: 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) in blood leukocytes and urine, and 8-oxo-7,8-dihydroguanine (8-oxoGua) in urine. The following parameters of vascular dysfunction were also examined: flow- (FMD) and nitroglycerin- (NMD) mediated dilatation of the brachial artery, pulse pressure (PP), distensibility coefficient (DC), pulsation (PI) and resistance (RI) index, carotid intima-media thickness (cIMT), and ankle-brachial index (ABI).ResultsIndividuals with an FMD value of ≥ 8.8% had significantly higher blood concentrations of antioxidative vitamins and lower concentrations of 8-oxodG in their urine and blood leukocytes than their counterparts. Blood concentration of alpha-tocopherol or ascorbic acid positively correlated with FMD, PI, RI, DC and ABI and negatively with PP and cIMT. The reverse was the case for 8-oxodG in urine and leukocytes. In multiple regression analysis, markers of oxidative DNA damage positively determined the variance in PP and ABI.ConclusionsIn persons without clinical manifestation of atherosclerosis, oxidative stress was an independent factor associated with vascular wall dysfunction, and a better predictor than smoking and blood concentrations of glucose, lipids and creatinine.

Correlation between vascular endothelial function parameters with indicators of suboptimal health status and the factors of cardiovascular risk

The problem of prevention of chronic non-communicable diseases continues to be relevant. It is a promising non-invasive integration of new screening methods to assess the patient's health system. The goal was to establish the relationship of vascular endothelial function parameters with indicators of suboptimal health status and the factors of cardiovascular risk. Materials and methods. A total of 327 residents of Samara, who had no history of disease and did not receive treatment in the last 3 months. We used a questionnaire diagnostic screening suboptimal health status SHSQ-25, the risk factors of cardiovascular diseases, endothelin-1, human blood index of endothelial function was determined by computer photopletismography. Results and discussion. Suboptimal health status is associated with the prevalence and severity of cardiovascular risk factors, smoking, overweight, total cholesterol, glucose, blood endothelin, vascular endothelium reactivity, indicating that their dominant influence on the quality of life in a population of healthy individuals. Vascular reactivity non-invasively evaluated in terms of endothelial function in the sample with ischaemia of the upper limb by computer photopletismography reflects systemic vascular endothelial function as a negative associated with endothelin blood and the main factors of cardiovascular risk: age, male gender, body mass index, the nature of work activity, blood pressure value.

Maternal vascular responses to hypoxia in a rat model of intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is a common pregnancy complication and is a leading cause of fetal morbidity and mortality. Placental hypoxia contributes to adverse fetal consequences, such as IUGR. Exposing pregnant rats to hypoxia can lead to IUGR; however, assessment of maternal vascular function in a rat model of hypoxia, and the mechanisms that may contribute to adverse pregnancy outcomes, has not been extensively studied. We hypothesized that exposing pregnant rats to hypoxia will affect maternal systemic vascular function and increase the uterine artery resistance index (RI), which will be associated with IUGR. To test this hypothesis, pregnant rats were kept in normoxia (21% O2) or hypoxia (11% O2) from gestational day (GD) 6 to 20 Maternal blood pressure, uteroplacental resistance index (RI) (ultrasound biomicroscopy), and vascular function (wire myography) were assessed in uterine and mesenteric arteries. Fetal weight was significantly reduced (P < 0.001), while maternal blood pressure was increased (P < 0.05) in rats exposed to hypoxia. Maternal vascular function was also affected after exposure to hypoxia, including impaired endothelium-dependent vasodilation responses to methacholine in isolated uterine arteries (pEC50 normoxia: 6.55 ± 0.23 vs. hypoxia: 5.02 ± 0.35, P < 0.01) and a reduced uterine artery RI in vivo (normoxia: 0.63 ± 0.04 vs. hypoxia: 0.53 ± 0.01, P < 0.05); associated with an increase in umbilical vein RI (normoxia: 0.35 ± 0.02 vs. hypoxia: 0.45 ± 0.04, P < 0.05). These data demonstrate maternal and fetal alterations in vascular function due to prenatal exposure to hypoxia. Further, although there was a compensatory reduction in uterine artery RI in the hypoxia groups, this was not sufficient to prevent IUGR.

Wild blueberry consumption attenuates local inflammation in the perivascular adipose tissue of obese Zucker rats

Perivascular adipose tissue (PVAT) has been shown to play important roles in regulating vascular tone and linking local and systemic vascular inflammation. We examined the impact of PVAT on phenylephrine-mediated vasoconstriction in the aorta of obese Zucker rats (OZR) and their lean littermates (LZR) by comparing aortic rings with or without PVAT. Subsequently we placed OZR and LZR on a control (C) or an 8% wild blueberry (WB) diet and evaluated the effect of WB consumption on such response. PVAT-released adipokine concentrations were also measured as a function of WB diet. Maximal constrictor force (Fmax) in aortic rings without PVAT was significantly lower in OZR-C compared with LZR-C (0.41 ± 0.05 and 0.71 ± 0.06 g, respectively). Following WB diet, Fmax significantly increased in OZR (0.54 ± 0.06 g). In aortas with intact PVAT, Fmax was significantly lower in all groups (0.31 ± 0.06 OZR-C, 0.30 ± 0.05 OZR-WB, 0.29 ± 0.03 LZR-C, and 0.30 ± 0.04 g LZR-WB), but no difference was observed between treatments. PVAT concentrations of monocyte chemoactractant protein 1 (MCP-1), tumor necrosis factor alpha, and adiponectin were significantly higher in OZR compared with LZR (+102%, +108%, and +45%, respectively). Following WB diet, PVAT concentrations of interleukin-8 were significantly lower in both OZR (-37%) and LZR (-30%), while adiponectin concentrations significantly increased in both OZR (+11%) and LZR (+16%). MCP-1 concentrations significantly decreased (-31%) in the PVAT of OZR with the WB diet. WB consumption appears to attenuate local inflammation in PVAT, which may impact systemic vascular inflammation and endothelial function.

SY 11-4 CONNECTIVE TISSUE DISEASE AND ITS ASSOCIATION WITH ARTERIAL HYPERTENSION

Connective tissue diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, and scleroderma, have a strong predilection for women and are associated with a marked increase in the prevalence of hypertension. The mechanisms leading to the increased risk of hypertension in these patients remain unclear; however, they are likely related to immune mediated changes in cardiovascular and renal function. Over the past several years, we have elucidated a number of factors that contribute to the development of hypertension during SLE using a widely established experimental model of SLE, the female NZBWF1 mouse. These factors include impaired systemic vascular function, altered renal hemodynamics, and increased oxidative stress and inflammatory cytokines. Recent work from our laboratory has focused on identifying fundamental immunological changes during SLE that ultimately lead to increased cardiovascular risk. This presentation will review clinical and basic evidence for the risk of hypertension during connective tissue diseases and provide experimental evidence that autoantibodies have a central mechanistic role in the pathogenesis of hypertension associated with SLE.

Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction.

BackgroundThe gut microbiome is essential for physiological host responses and development of immune functions. The impact of gut microbiota on blood pressure and systemic vascular function, processes that are determined by immune cell function, is unknown.Methods and ResultsUnchallenged germ‐free mice (GF) had a dampened systemic T helper cell type 1 skewing compared to conventionally raised (CONV‐R) mice. Colonization of GF mice with regular gut microbiota induced lymphoid mRNA transcription of T‐box expression in T cells and resulted in mild endothelial dysfunction. Compared to CONV‐R mice, angiotensin II (AngII; 1 mg/kg per day for 7 days) infused GF mice showed reduced reactive oxygen species formation in the vasculature, attenuated vascular mRNA expression of monocyte chemoattractant protein 1 (MCP‐1), inducible nitric oxide synthase (iNOS) and NADPH oxidase subunit Nox2, as well as a reduced upregulation of retinoic‐acid receptor‐related orphan receptor gamma t (Rorγt), the signature transcription factor for interleukin (IL)‐17 synthesis. This resulted in an attenuated vascular leukocyte adhesion, less infiltration of Ly6G+ neutrophils and Ly6C+ monocytes into the aortic vessel wall, protection from kidney inflammation, as well as endothelial dysfunction and attenuation of blood pressure increase in response to AngII. Importantly, cardiac inflammation, fibrosis and systolic dysfunction were attenuated in GF mice, indicating systemic protection from cardiovascular inflammatory stress induced by AngII.ConclusionGut microbiota facilitate AngII‐induced vascular dysfunction and hypertension, at least in part, by supporting an MCP‐1/IL‐17 driven vascular immune cell infiltration and inflammation.

Effects of transradial coronary catheterization on systemic and local vascular endothelial function and inflammatory process

Effects of transradial coronary catheterization on systemic and local vascular endothelial function and inflammatory process

NONINVASIVE SYSTEMIC VASCULAR RESISTANCE AND CARDIOVASCULAR OUTCOMES IN THE COMMUNITY: THE FRAMINGHAM HEART STUDY

The interplay between systemic vascular resistance (SVR) and ventricular function is important in cardiovascular disease (CVD). We investigated the relationship of SVR determined by transthoracic echocardiography (eSVR) with CVD in persons with high and low blood pressures. We evaluated 2320

NETosis in cancer.

A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. Although the awareness of tumor-induced systemic effects has increased significantly in recent years, current knowledge is still mainly restricted to metastatic sites. Surprisingly little is known about the situation in organs that are not targets for metastasis or directly affected by the primary tumor. We therefore decided to look deeper into this relatively unexplored field of cancer research. For obvious reasons human biopsy material from tissues not affected by tumor cells, in an individual with cancer, are rare and mouse models therefore become important tools for such investigations. Using two different orthotopic and spontaneously metastasizing tumor models - the RIP1-Tag2 model for insulinoma with metastasis to the liver and the MMTV-PyMT model for mammary carcinoma with lung metastasis - we analyzed the presence of hematopoietic cells in organs which do not represent sites for primary tumor growth. There was a significant increase in the number of neutrophils in heart and kidneys of tumor-bearing mice compared to healthy individuals [1]. In mice with cancer, peripheral organs displayed systemic inflammation and impaired vascular function, which was restored upon neutrophil depletion. Platelet/neutrophil complexes, indicative of neutrophil extracellular traps (NETs), were found in kidney and heart from tumor-bearing mice, while these complexes were completely absent in the corresponding tissues from healthy mice. Indeed, analysis of peripheral blood confirmed the presence of neutrophils with extracellular DNA-tails in tumor-bearing mice.