The present study assessed the effect of nearby construction activity on the responses of rat middle cerebral arteries (MCA)to the endothelium-dependent vasodilator acetylcholine and the NO donor sodium nitroprusside (SNP) and the activity of MaxiK potassium channels in MCA smooth muscle cells from male Sprague–Dawley rats. Two monitoring systems were used to assess vibrations in the animal rooms during and immediately after construction activities near the research building where the animal facility is located. One was a commercially available system; the other was a Raspberry-Pi (RPi)–based vibration monitoring system designed in our laboratory that included a small computing unit attached to a rolling sensor (low sensitivity) and a piezoelectric film sensor (high sensitivity). Both systems recorded increased levels of vibration during construction activity outside the building. During the construction period, vasodilator responses to acetylcholine and SNP were abolished, and MaxiK single-channel current opening frequency and open-state probability in cell-attached patches of isolated MCA myocytes were dramatically decreased. Recovery of acetylcholine- and SNP-induced dilation was minimal in MCA from rats studied after completion of construction but housed in the animal facility during construction, whereas responses to acetylcholine and SNP were intact in rats purchased, housed, and studied after construction. Baseline levels of vibration returned after the completion of construction, concomitant with the recovery of normal endothelium-dependent vasodilation to acetylcholine and of NO sensitivity assessed by using SNP in MCA from animals obtained after construction. The results of this study indicate that the vibration associated with nearby construction can have highly disruptive effects on crucial physiologic phenotypes.
The master antioxidant and cell protective transcription factor nuclear factor (erythroid‐derived 2)‐like‐2 (Nrf2) plays a key role in maintaining redox homeostasis by binding to antioxidant response elements (ARE) in the promoter regions of multiple antioxidant genes. The goal of these experiments was to determine whether direct activation of Nrf2‐mediated antioxidant defenses with Protandim (~40 mg/m2 per day for 2 weeks): 1) ameliorates endothelial dysfunction and oxidative stress in cerebral arteries of Dahl salt‐sensitive (SS) rats fed high salt (HS; 4% NaCl) diet; 2) improves renal function; and 3), increases skeletal muscle microvessel density in HS‐fed SS rats. Protandim treatment restored endothelium‐dependent vasodilation in response to acetylcholine (ACh) in the middle cerebral artery (MCA) of SS rats fed HS diet, but failed to increase skeletal muscle microvessel density or improve glomerular injury scores. Nrf2 activation also led to elevated urinary albumin levels and increased protein casting in renal tubules of HS‐fed SS rats. Protandim downregulated the expression of the pro‐oxidative transcription factor Kruppel‐like factor 9 (Klf9) in cerebral arteries but upregulated Klf9 expression in kidneys of HS‐fed SS rats fed HS diet. These findings support the hypothesis that pharmacological activation of Nrf2 during high and sustained levels of oxidative stress can have either beneficial effects (cerebral arteries) or detrimental effects that may be mediated by upregulation of Klf9 (kidney). These differential effects could have contributed to the failure of the BEACON clinical trial involving Nrf2 activation in patients with type 2 diabetes and advanced (stage 4) kidney disease; and may provide safety guidelines for therapeutic administration of Nrf2 activators in conditions characterized by elevated oxidative stress.Support or Funding InformationNIH #R01‐HL128242 and #R21‐OD018309‐JHLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The present study assessed the effect of nearby construction activity on endothelium‐dependent vasodilation to acetylcholine (ACh), a crucial diagnostic test, in middle cerebral arteries (MCA) of male Sprague‐Dawley (S‐D) rats. Construction activity began on October 2, 2017 and consisted of installing a utility tunnel for a new heating system near the MCW basic science building, followed by additional construction in front of the adjacent medical education building. The project involved extensive digging and tunneling, and the use of heavy equipment (steam shovels, bulldozers, dump trucks, front end loaders, etc.). Various construction activities continued until the end of May 2018. Most of the construction activity generated high levels of vibration and noise in the patio area just outside the MCW Biomedical Resource Center, which houses numerous rodents and other species used in research projects at the institution. Vibrations were monitored using a system (RPi) designed in our laboratory and consisting of a small computing unit attached to a rolling sensor (low sensitivity) and a Piezo Film Sensor (high sensitivity). The sensor was placed in an empty rat cage and vibrations were quantified as Hz. During the construction period, normal endothelium‐dependent vasodilation in response to ACh was abolished or dramatically reduced in isolated MCA of S‐D rats fed a normal salt diet. MCA from rats studied after completion of construction but housed in the vivarium during construction showed a partial recovery of ACh‐induced dilation, but MCA responses to ACh and vascular NO sensitivity, assessed via vasodilator responses to the NO donor sodium nitroprusside (SNP), in those animals were significantly reduced compared to rats obtained, housed, and studied after completion of the construction project. In separate experiments, activity of Ca2+‐activated maxi K+ channels was lost in isolated cerebral artery smooth muscle cells from S‐D rats housed and studied during the construction period. During the construction period, the RPi system recorded high levels of vibration that corresponded to construction activity outside the building. Following cessation of construction, baseline levels of vibration returned and endothelium‐dependent vasodilation to ACh and vessel NO sensitivity recovered to normal levels. The results of this study show that the noise and vibration associated with nearby construction can have highly deleterious effects upon crucial physiological phenotypes.Support or Funding InformationNIH #R01‐HL128242This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Objective: To determine if placental vessel endothelial dysfunction can be produced in control vessels by exposure to preeclamptic plasma, establishing a model to further explore the mechanisms of dysfunction and therapeutics to restore function in preeclampsia. Hypothesis: Preeclamptic plasma administered to unaffected vessels induces endothelial dysfunction. Methods: Placental microvessels were dissected from the maternal side of placentas from patients consented to the Medical College of Wisconsin Maternal Research Placenta and Cord Blood Bank. Control vessels were treated with 10% healthy maternal plasma or 10% preeclamptic (PreE) maternal plasma within the vessel lumen for 12-16 hours[MJ1]. PreE vessels were not treated with plasma. Microvessels were then cannulated on glass micropipettes, pressurized to 60mmHg and constricted with 0.1-1.0 nM Endothelin-1 (ET-1). A 1-100cm H2O pressure gradient was applied and the inner diameter of the vessel was measured by video microscopy. The change in diameter was calculated as a % of maximum diameter as assessed by exposure to 100μM papaverine. Flow mediated dilation (FMD) was evaluated by a two-way ANOVA test with Dunnett’s multiple comparisons. The maximum dilation values were evaluated by a Kruskal-Wallis test with Dunn’s multiple comparative test or t-test as appropriate. FMD is evaluated as mean +/- SEM. Data: Control vessels at maximum flow dilated to 81.1 % ± 7.1 % (n=5), whereas vessel from PreE placentas dilated to 36.9 % ± 8.6% (n=3,). Incubation of control vessels with normal plasma resulted in maximal dilation of 80.6% ± 3.3%, n=3. Control vessels incubated with plasma from PreE patients dilated to 44.7% ± 4.7%. n=3). Summary of Results: Control vessels dilated significantly more than PreE vessels when evaluated by t-test (p=0.05). Incubation of control vessels with normal plasma did not change maximal dilation (p>0.99). Control vessels incubated with PreE plasma demonstrated a near significant drop in dilatory capacity (p=0.05). PreE plasma exposed vessels compared to untreated PreE vessels showed no significant difference (p=0.46[DDG2] ).When comparing overall flow mediated dilatory responses in these vessels there is a significant difference observed between control vessels, control vessels treated with PreE plasma, and PreE vessels at 50cm H2O (p<0.05). This difference is even more significant (p<0.01) at the maximum pressure gradient when analyzed by two-way ANOVA. There is no significant difference at any point between control vessels and control vessels treated with normal plasma as evaluated by two-way ANOVA (p>0.99). Conclusions: The addition of PreE plasma to control vessels demonstrates similar impairment in endothelium-dependent vasodilation as seen in untreated PreE vessels. Future directions will include evaluation of the mechanisms of vasodilation and therapeutic options that could restore endothelial function in PreE vessels. NHLBI 1K08HL150340-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
BACKGROUNDHigh salt (HS) diet promotes vascular oxidative stress and endothelial dysfunction in animal models and humans. Studies in animals indicate that salt‐induced suppression of antioxidant defense mechanisms plays a crucial role in endothelial dysfunction, microvascular rarefaction and vascular oxidative stress. We hypothesized that activation of the master antioxidant transcription factor nuclear factor (erythroid‐derived 2)‐like‐2 (NRF2) with the dietary supplement Protandim protects against salt‐induced vascular dysfunction and microvascular rarefaction by restoring redox homeostasis.OBJECTIVETo determine whether activation of Nrf2 via dietary supplementation with Protandim will prevent salt‐induced endothelial dysfunction, vascular oxidative stress, and microvascular rarefaction via effects on antioxidant enzyme expression.METHODSAge‐matched, male Sprague‐Dawley rats (12–15 weeks old) were fed a high salt (HS; 4.0% NaCl) diet ± ~60 mg/kg/day Protandim supplement for 2 weeks. mRNA from harvested liver samples was used for real time PCR evaluation of the effects of Nrf2 upregulation on a range of genes related to oxidative stress, as reported in the literature. Changes in protein expression were evaluated via Western blotting.RESULTSProtandim treatment restored endothelium‐dependent dilation to acetylcholine in middle cerebral arteries, reduced mitochondrial ROS levels (Mito‐SOX) in basilar arteries, and increased microvessel density in the cremaster muscle of HS‐fed rats. Protandim supplementation increased mRNA levels of thioredoxin reductase 1 (n=6, p=0.008), reduced mRNA expression of the pro‐oxidative transcription factor Kruppel‐like factor 9 (Klf9) (n=6, p < 0.001) and tended to increase the expression of mRNA for glutathione reductase (GSR) and catalase in liver samples compared to untreated rats fed HS diet alone. Other indicators were not significantly changed by Protandim treatment, either by qPCR or Western blot analysis.CONCLUSIONSTreatment of HS‐fed rats with the Nrf2 activator Protandim ameliorates salt‐induced endothelial dysfunction, vascular oxidative stress, and microvascular rarefaction via complex effects on enzymes and proteins affecting redox state.Support or Funding InformationNIH #R01‐HL128242 and # R21‐OD018309‐JHLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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