Endothelium-dependent Vascular Reactivity Research Articles

Nanoparticle-mediated delivery of tetrahydrobiopterin restores endothelial function in diabetic rats

Endothelial dysfunction, underlying the vascular complications of diabetes and other cardiovascular disorders, may result from uncoupling of endothelial nitric oxide synthase (eNOS) activity due to decreased levels of tetrahydrobiopterin (BH4), a critical co-factor for eNOS. Some clinical trials attempting to deliver exogenous BH4 as a potential therapeutic strategy in vascular disease states have failed due to oxidation of BH4 in the circulation. We sought to develop a means of protecting BH4 from oxidation while delivering it to dysfunctional endothelial cells. Polymeric and solid lipid nanoparticles (NPs) loaded with BH4 were delivered by injection or oral gavage, respectively, to streptozotocin-induced diabetic rats. BH4 was measured in coronary endothelial cells and endothelium-dependent vascular reactivity was assessed in vascular rings. Lymphatic uptake of orally delivered lipid NPs was verified by sampling mesenteric lymph. BH4-loaded polymeric NPs maintained nitric oxide production by cultured endothelial cells under conditions of oxidative stress. BH4-loaded NPs, delivered via injection or ingestion, increased coronary endothelial BH4 concentration and improved endothelium-dependent vasorelaxation in diabetic rats. Pharmacodynamics assessment indicated peak concentration of solid lipid NPs in the systemic bloodstream 6 hours after ingestion, with disappearance noted by 48 hours. These studies support the feasibility of utilizing NPs to deliver BH4 to dysfunctional endothelial cells to increase nitric oxide bioavailability. BH4-loaded NPs could provide an innovative tool to restore redox balance in blood vessels and modulate eNOS-mediated vascular function to reverse or retard vascular disease in diabetes.

MATERNAL SALT INTAKE AND MICROVASCULAR ENDOTHELIAL FUNCTION DURING THE THIRD TRIMESTER OF HEALTHY PREGNANCY

Objective: Even in healthy individuals, high-salt (HS) loading leads to endothelial dysfunction, a hallmark of cardiometabolic diseases, independently of the changes in blood pressure (BP). Still, the effect of the amount of daily salt intake during healthy pregnancy on maternal endothelium-dependent vascular reactivity has not yet been investigated. Thus, this study aimed to assess the effect of the amount of daily salt intake during third trimester of pregnancy on maternal microvascular reactivity to stimuli in healthy pregnant women. Design and method: The present study was designed as a cross-sectional study in which all the data for each pregnant woman were obtained at one-time point between 37 and 40 weeks of gestation. Daily salt intake was estimated based on 24-h urinary sodium excretion using appropriate formula [1-g salt (NaCl) = 393.4 mg Na = 17.1 mmol Na]. Microvascular endothelium-dependent vasodilation in response to vascular occlusion (PORH), iontophoresis of acetylcholine (AChID) and local heating (HEAT), as well as endothelium-independent vasodilation in response to iontophoresis of sodium nitroprusside (SNP) was assessed by Laser Doppler flowmetry (LDF). Results: Preliminary results of the present study involve data obtained from 27 healthy pregnant women. According to the amount of daily salt intake, pregnant women were divided in low-salt (LS, < 5 g of salt/day, N = 4), normal-to-high salt (NHS, 5.0–7.5 g of salt/day, N = 12) and high-salt (HS, > 7.5 g of salt/day, N = 11) group. All pregnant women were normotensive, and BP values did not differ between groups. HEAT was significantly lower in HS compared to LS and NHS group, while PORH and AChID tended to be lower in HS compared to LS and NHS group, but without statistical significance. SNPID did not significantly differ between the groups. There was weak to moderate negative correlation between daily salt intake and functional markers of microvascular endothelium-dependent vasodilation (PORH, AChID and HEAT). Conclusions: The amount of daily salt intake significantly affects maternal endothelium-dependent microvascular reactivity during third trimester of healthy pregnancy, i.e. the increased salt intake significantly reduces the endothelium-dependent dilatation of the skin microcirculation, especially responses mediated by nitric-oxide (NO).

Endothelial-Dependent Responses Correlate with Pediatric SOFA Scores During Severe Sepsis and Septic Shock.

Sepsis is an exaggerated host response to an infectious challenge that is associated with significant alterations in vasomotor tone. We hypothesized that the endothelial dysfunction observed during severe sepsis and septic shock would correlate with the degree of organ failure as determined by the pediatric Sequential Organ Failure Assessment (pSOFA) score. Utilizing laser Doppler perfusion monitoring coupled with iontophoresis, we found that endothelium-dependent vascular reactivity to acetylcholine (ACh) stimulation significantly correlated with both total pSOFA scores and, more specifically, cardiovascular (CV) pSOFA scores. Alternatively, endothelium-independent vascular reactivity using sodium nitroprusside (SNP) did not demonstrate a significant relationship with pSOFA scores. These data suggest that endothelial-mediated vasculopathy may be a key driver of organ dysfunction during episodes of pediatric sepsis.

Low-dose angiotensin II supplementation restores flow-induced dilation mechanisms in cerebral arteries of Sprague-Dawley rats on a high salt diet.

Salt-induced suppression of angiotensin II contributes to impaired endothelium-dependent vascular reactivity. The present study investigated the effect of chronic low-dose angiotensin II (ANG II) supplementation on the mechanisms of flow-induced dilation (FID) and oxidative stress at the cellular and molecular level in middle cerebral arteries (MCA) of male Sprague-Dawley rats fed high salt diet. Rats (10 weeks old) were randomly assigned to a low salt diet group (0.4% NaCl in rat chow); high salt diet group (7 days 4% NaCl in rat chow) or HS+ANG II group [7 days high salt diet with 3 days ANG II administration via osmotic minipumps (100 ng/kg per min on days 4-7)]. FID was determined in absence/presence of the NOS inhibitor L-NAME, the non-selective cyclooxygenase (COX-1,2) inhibitor indomethacin, a selective inhibitor of CYP450 epoxygenase activity (MS-PPOH) and the superoxide dismutase mimetic TEMPOL. Gene expression of antioxidative enzymes, and of genes and proteins involved in FID mechanisms were determined by RT-qPCR and western blot. Vascular nitric oxide and superoxide/reactive oxygen species levels were assessed by direct fluorescence. Serum systemic oxidative stress parameters were measured by spectrophotometry. Chronic low-dose ANG II supplementation in high salt fed rats restored FID of MCAs, which was nitric oxide, prostanoid and epoxyeicosatrienoic acid dependent. ANG II changed the protein/gene expression of COXs, HIF-1α and VEGF and significantly increased GPx4 and EC-SOD antioxidative enzyme expression, decreased systemic oxidative stress, decreased superoxide/ROS levels and increased nitric oxide bioavailability in the vascular wall. Physiological levels of circulating ANG II are crucial to maintain the HIF-1α dependent mechanisms of FID and vascular oxidative balance without affecting mean arterial pressure.

The Inverse Relationship Between Endothelium-Dependent Vasodilation and Blood Pressure is Lost After Cardiopulmonary Bypass.

Cardiopulmonary bypass (CPB) is required for the surgical correction of congenital heart defects and incites an acute inflammatory response that impairs endothelial function post-operatively. Therefore, we hypothesized that the pre-operative relationship between endothelial function and blood pressure would be impaired after CPB-mediated inflammation. Using laser Doppler perfusion monitoring coupled with iontophoresis, we found that while there was a significant inverse correlation between endothelium-dependent vascular reactivity to acetylcholine (ACh) stimulation and systolic blood pressure (SBP), this relationship was lost after CPB. No relationship was observed between endothelium-independent vascular reactivity using sodium nitroprusside (SNP) and SBP either pre-CPB or any point thereafter. Additionally, neither CPB time nor inflammatory cytokines correlated with the degree of responsiveness to ACh. These data suggest that the measurement of endothelium impairment after CPB may be more reflective of cardiovascular health than SBP alone.

Periodontal status, vascular reactivity, and platelet aggregation changes in rats submitted to hypercholesterolemic diet and periodontitis

Periodontitis can corroborate with development and progression of atherosclerosis and a possible bidirectional interaction between both pathologies has been hypothesized. The aim of this work was to study the interactions between diet-induced hypercholesterolemia and ligature-induced periodontitis in Wistar rats submitted to both conditions. Animals were divided into four experimental groups: C (control: standard diet without periodontitis), Perio (periodontitis plus standard diet), HC (high cholesterol diet without periodontitis), and HC+Perio (high cholesterol diet plus periodontitis). The diets were offered for 45days and a silk ligature was applied in the lower first molars of Perio and HC-Perio animals on day 34 and maintained for 11days until euthanasia. The mandibles were excised, and alveolar bone loss was determined by macroscopic and micro-tomographic (µ-CT) imaging. Blood samples were obtained, and platelet aggregation was induced in plasma rich in platelets by adenosine diphosphate (ADP) and collagen. Endothelium-dependent vascular reactivity and protein expression of endothelial (eNOS), phosphorylated endothelial (peNOS), and inducible (iNOS) nitric oxide synthases were evaluated in aorta samples. The HC diet combined with periodontitis (HC+Perio group) was associated with an increased alveolar bone loss, when compared to the other groups. Both in Perio and HC groups, platelet aggregation induced by ADP or collagen was increased, while maximum aortic relaxation induced by acetylcholine was decreased. Periodontitis or HC diet alone decreased the expression of peNOS and HC diet increased the expression of iNOS. In contrast, no additive or synergistic effects were found in vascular reactivity or in platelet aggregation when the two conditions were associated (HC+Perio group). Hypercholesterolemia accelerated the process of bone loss induced by periodontitis while a high cholesterol diet or periodontitis individually increased platelet aggregation and vascular reactivity in rats without additive or synergistic effects, when associated.

Vildagliptin, a DPP-4 Inhibitor, Attenuates Endothelial Dysfunction and Atherogenesis in Nondiabetic Apolipoprotein E-Deficient Mice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel antidiabetic agents with possible vascular protection effects. Endothelial dysfunction is an initiation step in atherogenesis. The purpose of this study was to investigate whether vildagliptin (Vilda) attenuates the development of endothelial dysfunction and atherosclerotic lesions in nondiabetic apolipoprotein E-deficient (ApoE-/-) mice. Eight-week-old nondiabetic ApoE-/- mice fed a Western-type diet received Vilda (50 mg/kg/day) for 20 weeks or 8 weeks. After 20 weeks of treatment, Vilda administration reduced atherogenesis in the aortic arch as determined by en face Sudan IV staining compared with the vehicle group (P < 0.05). Vilda also reduced lipid accumulation (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) expression (P < 0.05) and tended to decrease macrophage infiltration (P = 0.05) into atherosclerotic plaques compared with vehicle. After 8 weeks of treatment, endothelium-dependent vascular reactivity was examined. Vilda administration significantly attenuated the impairment of endothelial function in nondiabetic ApoE-/- mice compared with the vehicle group (P < 0.05). Vilda treatment did not alter metabolic parameters, including blood glucose level, in both study protocols. To investigate the mechanism, aortic segments obtained from wild-type mice were incubated with exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analog, in the presence or absence of lipopolysaccharide (LPS). Ex-4 attenuated the impairment of endothelium-dependent vasodilation induced by LPS (P < 0.01). Furthermore, Ex-4 promoted phosphorylation of eNOS at Ser1177 which was decreased by LPS in human umbilical endothelial cells (P < 0.05). Vilda inhibited the development of endothelial dysfunction and prevented atherogenesis in nondiabetic ApoE-/- mice. Our results suggested that GLP-1-dependent amelioration of endothelial dysfunction is associated with the atheroprotective effects of Vilda.

In vitro evidence that endothelium-dependent vasodilatation induced by clozapine is mediated by an ATP-sensitive potassium channel.

There is a definite association between antipsychotic drugs and arterial hypertension. However, endothelium functions are scarcely considered. This investigation was carried out to study the mechanisms involved in clozapine endothelium-dependent vascular reactivity. The experimental animals were male Wistar rats with a mean age of 70-90 days (250-300 g). The endothelium-dependent vascular reactivity was studied by measuring the isometric force and then constructing clozapine concentration-response curves. The force registrations were obtained in the aorta rings with and without the endothelium precontracted with phenylephrine (PE10-6M) treatment; this followed incubation for 30 min in "organ chambers" with different inhibitors: l- NAME (nitric oxide/cGMP); indomethacin (PGI2/cAMP); tetraethylammonium (TEA), and specific hyperpolarization blockers (paxillin, apamin, glibenclamide). The data were presented as the mean ± standard error of the mean (SEM) and were compared by one-way ANOVA or two-way ANOVA followed by the Bonferroni post-test. The primary outcomes were: 1) Clozapine-induced endothelium-dependent relaxation was not inhibited by indomethacin, l-NAME, ODQ, and methylene blue (MB); 2) The combination of l-NAME + indomethacin partially prevented the relaxation; 3) Clozapine did not induce relaxation in vessels contracted with KCl; 4) TEA did not block the clozapine-induced relaxation in vessels precontracted with PE (10-6 M); 5) The potassium channel blockers paxillin and apamin did not prevent relaxation but glibenclamide did. Concerning the mechanisms involved in clozapine endothelium-dependent vascular reactivity, the present study suggests that there is synergistic participation that probably occurs through a crosstalk mechanism of the cAMP, cGMPpathways and hyperpolarization.

Vasoreactivity to Acetylcholine During Porcine Kidney Perfusion for the Assessment of Ischemic Injury

BackgroundThe effects of renal allograft ischemic injury on vascular endothelial function have not been clearly established. The aim of this study was to examine vascular reactivity to acetylcholine (ACh) in kidneys subjected to ischemic injury and reperfusion. MethodsPorcine kidneys were exposed to different combinations of warm ischemic time (WIT) and cold ischemic time (CIT) as follows: 15 min (n = 7), 60 min (n = 6), 90 min (n = 6), or 120 min (n = 4) WIT + 2 h CIT or 15 min WIT + 16 h CIT (n = 8). Kidneys were reperfused at 38°C for 3 h. After reperfusion, ACh was infused into the circuit to assess endothelium-dependent vascular reactivity. ResultsThe dose-response relationships between renal blood flow and ACh demonstrated that ACh doses of 10−10 to 10−7 mmol/L caused vasodilatation, whereas doses in the range 10−6 to 10−4 mmol/L led to vasoconstriction. For kidneys exposed to 15-90 min WIT, there was a clear relationship between increasing ischemic injury and reduced vasodilatation to ACh. In contrast, kidneys subjected to 120 min WIT completely lost vasoreactivity. The vasodilatory response to ACh was diminished, but not lost, when CIT was increased from 2 h to 16 h. Peak renal blood flow after ACh infusion correlated with the functional parameters in kidneys with 2 h CIT (P < 0.05). ConclusionsThe loss of renal vascular reactivity after 120 min WIT suggests endothelial dysfunction leading to loss of nitric oxide synthesis/release. Measurement of vasoreactivity to ACh in an isolated organ perfusion system has the potential to be developed as a marker of ischemic renal injury before transplantation.

ENDOTHELIUM-DEPENDENT VASCULAR REACTIVITY IN DIABETES MELLITUS TYPE 2

The review presents modern information on the development of disorders of endothelium-dependent vascular reactivity in diabetes mellitus (DM) type 2. In type 2 DM, disorders of endothelium-dependent vascular reactivity associated with hyperglycemia and oxidative stress, manifesting by a reduced vascular response to vasodilators and pressor (paradoxical) vascular reactions to them, directly associated with cardiovascular events are observed.

Assessing Microvascular Function in Humans from a Chronic Disease Perspective

Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro)vascular reactivity can be studied. This reactivity depends on the balance between various mediators, including nitric oxide, endothelin, and prostanoids, among others. The measurement of microvascular (endothelial) function is important to understand the pathophysiologic mechanisms that contribute to MVD and the role of MVD in the development and progression of cardiometabolic/renal disease. Here, we review a selection of direct, noninvasive techniques for measuring human microcirculation, with a focus on methods, interpretation, and limitations from the perspective of chronic cardiometabolic and renal disease.

Presentation of an experimental method to induce in vitro ("organ chambers") respiratory acidosis and its effect on vascular reactivity.

To create in vitro a model to generate acidosis by CO2 bubbling "organ chambers", which would be useful for researchers that aim to study the effects of acid-base disturbs on the endothelium-dependent vascular reactivity. Eighteen male Wistar rats (230-280 g) were housed, before the experiments, under standard laboratory conditions (12h light/dark cycle at 21°C), with free access to food and water. The protocol for promoting in vitro respiratory acidosis was carried out by bubbling increased concentrations of CO2. The target was to achieve an ideal way to decrease the pH gradually to a value of approximately 6.6.It was used, initially, a gas blender varying concentrations of the carbogenic mixture (95% O2 + 5% CO2) and pure CO2. 1) 100% CO2, pH variation very fast, pH minimum 6.0; 2) 90%CO2 pH variation bit slower, pH minimum 6.31; 3) 70%CO2, pH variation slower, pH minimum 6.32; 4) 50% CO2, pH variation slower, pH minimum 6:42; 5) 40 %CO2, Adequate record, pH minimum 6.61, and; 6) 30 %CO2 could not reach values below pH minimum 7.03. Based on these data the gas mixture (O2 60% + CO2 40%) was adopted. This gas mixture (O2 60% + CO2 40%) was effective in inducing respiratory acidosis at a speed that made, possible the recording of isometric force.

Abstract 483: Mas/AT2 Receptor Deficient Mice Present A Pronounced Endothelial Dysfunction That Is Exclusively Mas-Related

The angiotensin type 2 (AT2) receptor and the angiotensin-(1-7) receptor MAS belong to the protective arm of the Renin Angiotensin System (RAS). They behave in a very similar way in terms of their physiological (tissue-protective) actions. Here we evaluate the endothelial function of Mas/AT2 double knockout mice (DKO) in two different backgrounds, C57BL/6 and FVB/N-C57BL/6 mixed background. Endothelial function in conscious mice was evaluated by measuring changes in mean arterial pressure (MAP) in response to bolus intra-aortic acetylcholine (ACh) and sodium nitroprusside (SNP) administration. The substances were given in 1μL per 10 g of body weight at the following doses: 25, 50, 100 ng/kg for ACh and 10 μg/kg for SNP. To correct the differences in vascular smooth muscle reactivity, the response to ACh was normalized by the SNP response. Our main results show that regarding the absolute response to ACh, Mas/AT2 DKO animals in both backgrounds had markedly decreased vasodilation response when compared with wild type (WT) over the dose range of 25 to 100 ng/kg (table 1). The MasKO animals had similar impairment of the vasodilatory response as the DKO mice when compared with WT animals, thus there was no statistical difference between the MasKO and DKO animals. No significant difference between the AT2KO and WT animals was observed in regard to the vasodilatory response to ACh. Normalization of ACh response with the SNP effect reinforced the observation that endothelium-dependent vascular reactivity was impaired. The evidence provided in this study suggests that the endothelial dysfunction observed in the Mas/AT2 DKO animals is exclusively due to the deletion of Mas.

Amyloid burden, neuroinflammation, and links to cognitive decline after ischemic stroke.

One in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and half without. After recurrent stroke, more than a third will become demented.1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms contribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets. Clinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia,3 and experimental studies with animals have addressed the relationship between stroke and AD.4–9 Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ1–42) accumulate in patients with multi-infarct dementia,10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilin-knockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity.9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arterial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in transgenic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute to the higher ischemia …

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Effects of Atorvastatin and Insulin in Vascular Dysfunction Associated With Type 2 Diabetes

Atorvastatin and insulin have distinct mechanisms of action to improve endothelial function. Therefore, we hypothesized that atorvastatin and insulin therapies alone or in combination could have beneficial effects on endothelium-dependent vascular reactivity, oxidative stress, inflammation and metabolic parameters in Goto-Kakizaki (GK) rats, a model of type 2 diabetes fed with atherogenic diet (GKAD). In parallel with the development of diabetes and lipid profile, the generation of oxidative stress was determined by measurement of lipid peroxides and oxidized proteins and the presence of inflammation was evaluated by assessing C-reactive protein (CRP). Additionally, endothelial dependent and independent vascular sensitivity to acetylcholine and sodium nitroprusside were evaluated. GKAD showed increased carbonyl stress, inflammation, fasting glycemia, dyslipidemia and endothelial dysfunction when compared to control GK rats. Noteworthy, supplementation with insulin deteriorated endothelial dysfunction while atorvastatin induced an improvement. Atorvastatin and insulin therapies in combination improved metabolic parameters, CRP levels and insulin resistance indexes and ameliorated endothelial dysfunction in GKAD rats while they were unable to reduce urinary 8-isoprostranes and plasma carbonyl compounds. The therapeutic association of atorvastatin and insulin provided a better metabolic control with a reduction in endothelial dysfunction in GKAD rats by a mechanism that involves an improvement in systemic inflammation.

Susceptibility to focal and global brain ischemia of Alzheimer mice displaying aβ deposits: effect of immunoglobulin.

Cerebral ischemia is a risk factor for Alzheimer's disease (AD). Moreover, recent evidence indicates that it is a two-way street as the incidence rate of stroke is significantly higher in AD patients than those without the disease. Here we investigated the interaction of ischemic brain insults and AD in 9-month-old ApdE9 mice, which show full-blown accumulation of Aβ deposits and microgliosis in the brain. Permanent occlusion of the middle cerebral artery (pMCAo) resulted in 36% larger infarct in ApdE9 mice compared to their wild-type (wt) controls. This was not due to differences in endothelium-dependent vascular reactivity. Treatment with human intravenous immunoglobulin (IVIG) reduced the infarct volumes and abolished the increased vulnerability of ApdE9 mice to pMCAo induced brain ischemia. When the mice were exposed to global brain ischemia (GI), an insult of hippocampal cells, ApdE9 mice showed increased neuronal loss in CA2 and CA3 subregions compared to their wt controls. GI was associated with increased microgliosis, astrogliosis, infiltration of blood-derived monocytic cells, and neurogenesis without clear differences between the genotypes. IVIG treatment prevented the GI-induced neuron loss in hippocampal CA1 and CA3 regions in ApdE9 mice. IVIG treatment increased microgliosis in wt but not in ApdE9 mice. Finally, GI induced 60% reduction in the hippocampal Aβ burden in ApdE9 mice, which was not affected by IVIG treatment. The results indicate that the AD pathology with Aβ deposits and microgliosis increases ischemic vulnerability in various brain areas. Moreover, IVIG treatment may be beneficial especially in patients suffering from both acute ischemic insult and AD.

The Link Between Unpredictable Chronic Mild Stress Model for Depression and Vascular Inflammation?

Inflammation has been suggested to be associated with stress-induced depression and cardiovascular dysfunction. Tumor necrosis factor alpha (TNF-α) is a major cytokine in the activation of neuroendocrine, immune, and behavioral responses. In this study, we investigated the effects of infliximab (a TNF-α inhibitor) on endothelium-dependent vascular reactivity, systemic blood pressure, and endothelial nitric oxide synthase (eNOS) immunoreactivity in the unpredictable chronic mild stress (UCMS) model of depression in rats. There was no significant change between all groups in the systemic blood pressure. In UCMS, endothelium-dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response (E max) and pD2 values compared with the controls. Infliximab was able to reverse this UCMS effect. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside and papaverine and KCl-induced contractile responses was similar between groups. In UCMS, decreased expression of eNOS was detected. Moreover, there was no significant change in UCMS + infliximab group with respect to control rats. Our results suggest that tumor necrosis factor-alpha (TNF-α) could be a major mediator of vascular dysfunction associated with UCMS, leading to decreased expression of eNOS.

Ethanolic extract of rhizome of Ligusticum chuanxiong Hort. (chuanxiong) enhances endothelium-dependent vascular reactivity in ovariectomized rats fed with high-fat diet.

The rhizome of Ligusticum chuanxiong Hort. (LC), also known as chuanxiong, is a very common herb widely used to treat cardiovascular and cerebrovascular diseases. It is also used as a major ingredient in soups for regular consumption to promote good health. To study the protective effect of LC ethanolic extract (LCEE, 600 mg per kg per day, p.o.) on the integrity of the vascular system, ovariectomized (OVX) rats were fed with a high-fat diet (HFD) plus LCEE for 12 weeks. The animal model was used to mimic the dyslipidemic condition seen in postmenopausal women. LCEE was found significantly to reduce the body weight gain, improve serum lipid profiles (by lowering total cholesterol and low density lipoprotein cholesterol but raising high density lipoprotein cholesterol) and protect vascular endothelium in the HFD-fed OVX rats. It is postulated that LCEE could exert its vascular protective effect through multiple targets by (1) improving serum lipid profiles to reduce the detrimental effects of cholesterol; (2) reducing the ROS level in the body via enhancing the hepatic anti-oxidative activity or antioxidant level to scavenge the reactive oxygen species generated in the postmenopausal hypercholesterolemic condition; (3) stimulating eNOS-derived nitric oxide production; (4) counteracting the up-regulation of inflammatory cytokine (TNF-α, VCAM-1 and ICAM-1) expressions so as to reduce endothelium damage.

Prenatal Testosterone Induces Sex-Specific Dysfunction in Endothelium-Dependent Relaxation Pathways in Adult Male and Female Rats1

Prenatal testosterone (T) exposure impacts postnatal cardiovascular function, leading to increases in blood pressure with associated decreased endothelium-dependent vascular relaxation in adult females. Endothelial function in males is not known. Furthermore, which of the endothelial pathways contributes to endothelial dysfunction and if there exists sex differences are not known. The objective of this study was to characterize the relative contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to the impaired endothelium-dependent vasodilation in prenatal T-exposed adult males and females. Offspring of pregnant rats treated with T propionate or its vehicle were examined. Telemetric blood pressure levels and endothelium-dependent vascular reactivity were assessed with wire myography. Levels of nitric oxide synthase (NOS3) and Kcnn3 and Kcnn4 channel expression were examined in mesenteric arteries. Mean arterial pressure was significantly higher in T males and females than in controls. Endothelium-dependent acetylcholine relaxation was significantly lower in both T males and females. EDHF-mediated relaxation was specifically blunted in T males (Emax = 48.64% ± 3.73%) compared to that in control males (Emax = 81.71% ± 3.18%); however, NO-mediated relaxation was specifically impaired in T females (Emax = 36.01% ± 4.29%) compared with that in control females (Emax = 54.56% ± 6.37%). Relaxation to sodium nitroprusside and levcromakalim were unaffected with T-treatment. NOS3 protein was decreased in T females but not in T males. Kcnn3 expression was decreased in both T males and females compared to controls. These findings suggest that prenatal T leads to an increase in blood pressure in the adult offspring, associated with blunting of endothelial cell-associated relaxation and that the effects are sex-specific: EDHF-related in males and NO-related in females.