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Antioxidants (Basel, Switzerland) Apr 2024The NADPH oxidase NOX4 that releases HO can mediate vasoprotective mechanisms under pathophysiological conditions in conductive arteries. However, the role of NOX4 in...
The NADPH oxidase NOX4 that releases HO can mediate vasoprotective mechanisms under pathophysiological conditions in conductive arteries. However, the role of NOX4 in resistance arteries and in perivascular adipose tissue is not well understood. We hypothesized that NOX4 is of functional importance in resistance arteries and perivascular adipose tissue under dyslipidemia conditions. We detected elevated expression in murine and human vessels under dyslipidemia. Diminishing under these conditions led to endothelial dysfunction in resistance arteries. The mesenteric arteries of / mice revealed decreased mRNA expression. Inhibition of eNOS in those vessels did not affect vascular function, while in mice endothelial function was significantly altered. Anticontractile properties of perivascular adipose tissue at resistance arteries were diminished in / compared with mice. In addition, the presence of perivascular adipose tissue further worsened endothelial dysfunction in mesenteric arteries under dyslipidemia conditions. Perivascular adipose tissue from mesenteric arteries revealed a higher expression of markers of white adipocytes compared to markers of beige/brown adipocytes. Among those white adipocyte markers, leptin was significantly less expressed in perivascular adipose tissue from / mice compared with mice. Furthermore, in human perivascular adipose tissue with a profound pattern of white adipocyte marker genes, we detected a correlation of and expression. In addition, incubating arterial vessels with leptin induced nitrite release, indicating increased eNOS activity. In humans, a higher expression of leptin in perivascular adipose tissue correlated with expression in the corresponding left internal mammary artery. In conclusion, vascular function of resistance arteries was dependent on -derived HO, especially under dyslipidemia conditions. Perivascular adipose tissue of the mesenteric arteries with white adipose tissue characteristics further aggravated endothelial function through reduced leptin-eNOS signaling.
PubMed: 38790608
DOI: 10.3390/antiox13050503 -
Kidney International May 2024Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated...
Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated intravascular coagulation and severe capillary vasospasm after cardiac death of rat kidneys. Additionally, we found a significant accumulation of fibrinogen in a hypoxic cell culture of human umbilical vein epithelial cells and in isolated kidneys exposed to prolonged warm ischemic following flushing out of blood. However, pre-flushing the kidney with snake venom plasmin in a 90-minute warm ischemic model maximized removal of micro thrombi and facilitated the delivery of oxygen and therapeutic agents. Application of carbon monoxide-releasing CORM-401 during ex vivo hypothermic oxygenated perfusion achieved multipath protective effects in prolonged warm ischemic kidneys. This led to significant improvements in perfusion parameters, restoration of the microcirculation, amelioration of mitochondrial injury, oxidative stress, and apoptosis. This benefit resulted in significantly prolonged warm ischemic kidney recipient survival rates of 70%, compared with none in those receiving ex vivo hypothermic oxygenated perfusion alone. Significantly, ex vivo hypothermic oxygenated perfusion combined with cytoprotective carbon monoxide releasing CORM-401 treatment meaningfully protected the donated kidney after cardiac death from ischemia-reperfusion injury by reducing inflammation, oxidative stress, apoptosis, and pathological damage. Thus, our study suggests a new combination treatment strategy to potentially expand the donor pool by increasing use of organs after cardiac death and salvaging prolonged warm ischemic kidneys.
PubMed: 38789038
DOI: 10.1016/j.kint.2024.04.018 -
Anesthesiology May 2024Hemorrhagic shock (HS) and rhabdomyolysis (RM) are two important risk factors of acute kidney injury (AKI) after severe trauma, however the effects of the combination of...
BACKGROUND
Hemorrhagic shock (HS) and rhabdomyolysis (RM) are two important risk factors of acute kidney injury (AKI) after severe trauma, however the effects of the combination of RM and HS on kidney function are unknown. The purpose of this study was to determine the impact of RM and HS on renal function, oxygenation, perfusion and morphology, in a pig model.
METHODS
Forty-seven female pigs were divided into 5 groups: sham, RM, HS, HS and moderate RM (RM4/HS), HS and severe RM (RM8/HS). RM was induced by intramuscular injection of Glycerol 50% with a moderate dose (4 ml/kg for RM4/HS group) or a high dose (8 ml/kg for RM and RM8/HS groups). Among animals with HS, after 90 min of hemorrhage, animals were resuscitated with fluid followed by transfusion of the withdrawn blood. Animals were followed for 48 hours. Macro and microcirculatory parameters measurements were performed.
RESULTS
RM alone induced a decrease in creatinine clearance at 48 hours (19 (0-41) vs 102 (56-116) ml/min for RM and SHAM respectively; p = 0.0006) without alteration in renal perfusion and oxygenation. HS alone impaired temporarily renal microcirculation, function and oxygenation that were restored with fluid resuscitation. RM4/HS and RM8/HS groups induced greater impairment of renal microcirculation and function than HS alone at the end of blood spoliation that were not improved by fluid resuscitation. Mortality was increased in RM8/HS and RM4/HS groups in the first 48 hours (73% vs 56% vs 9% for RM8/HS, RM4/HS and HS groups respectively).
CONCLUSIONS
The combination of HS and RM induced an early deleterious effect on renal microcirculation, function and oxygenation with decreased response to resuscitation and transfusion compared with HS or RM alone.
PubMed: 38787807
DOI: 10.1097/ALN.0000000000005097 -
American Journal of Physiology. Heart... Jul 2024Brachial artery flow-mediated dilation (BAFMD) is induced by hyperemic wall shear rate (WSR) following forearm ischemia. In older adults, there appears to be a reduced... (Comparative Study)
Comparative Study
Brachial artery flow-mediated dilation (BAFMD) is induced by hyperemic wall shear rate (WSR) following forearm ischemia. In older adults, there appears to be a reduced brachial hyperemic WSR and altered stimulus-response relationship compared with young adults. However, it is unclear if an altered forearm microvascular response to ischemia influences brachial hyperemic WSR in older adults. We determined associations between brachial hyperemic WSR and forearm skeletal muscle oxygen saturation in young and older adults. Healthy young ( = 17, 29 ± 7 yr) and older ( = 32, 65 ± 4 yr) adults participated in the study. BAFMD by a multigate spectral Doppler system and forearm skeletal muscle oxygen saturation by near-infrared spectroscopy were concurrently measured. When compared with the young, older adults showed reduced oxygen extraction kinetics (OE, 0.15 [0.12-0.17] vs. 0.09 [0.05-0.12]%s) and magnitude (So, 3,810 ± 1,420 vs. 2,723 ± 1,240%s) during ischemia, as well as oxygen resaturation kinetics (So, 2.5 ± 0.7 vs. 1.7 ± 0.7%s) upon reperfusion (all < 0.05). When OE in the young and So in older adults were stratified by their median values, young adults with OE above the median had greater hyperemic WSR parameters compared with those below the median ( < 0.05), but So in older adults did not show clear differences in hyperemic WSR parameters between those above/below the median. This study demonstrates that, in addition to a reduced microvascular response to ischemia, there may be a dissociation between microvascular response to ischemia and brachial hyperemic WSR in older adults, which may result in a further impairment of BAFMD in this cohort. Microvascular response to ischemia and subsequent reperfusion is diminished in older adults compared with the young. Furthermore, there appears to be a dissociation between the microvascular response to ischemia and brachial hyperemic WSR in older adults, which may further disturb the BAFMD process in this cohort. A reduced BAFMD in older adults may be a result of multiple alterations occurring both at macro- and microcirculation.
Topics: Humans; Brachial Artery; Male; Female; Vasodilation; Adult; Aged; Hyperemia; Muscle, Skeletal; Regional Blood Flow; Middle Aged; Microcirculation; Forearm; Young Adult; Ischemia; Age Factors; Blood Flow Velocity; Spectroscopy, Near-Infrared; Aging; Oxygen Consumption; Oxygen Saturation; Microvessels
PubMed: 38787380
DOI: 10.1152/ajpheart.00158.2024 -
Biology Apr 2024Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can...
Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can occur with or without cardiac compromise. One of the possible causes of stroke development is microvascular commitment. Our group previously described that experimental acute infection leads to cerebral microvasculopathy. This condition is characterized by decreased capillary density, increased leukocyte rolling and adhesion, and endothelial dysfunction. CD was discovered 114 years ago, and until today, only two drugs have been available for clinical treatment: benznidazole and nifurtimox. Both present a high cure rate for the acute phase (80%) and small cure rate for the chronic phase (20%). In addition, the high occurrence of side-effects, without proper medical follow-up, can result in treatment abandonment. Therefore, the search for new therapeutic schemes is necessary. Statins are drugs already used in the clinic that have several pleiotropic effects including endothelial function improvement, anti-inflammatory action, as well as trypanocidal effects, making them a potential alternative treatment for brain microvasculopathy in CD. Here, we investigate the effect of lovastatin (LOV) on brain microvasculopathy and inflammatory parameters. Swiss Webster mice were intraperitoneally inoculated with the Y strain of . Treatment with lovastatin (20 mg/kg/day) was initiated 24 h after the infection and continued for 14 consecutive days. We observed that LOV treatment did not affect parasitemia, brain microcirculation alterations, or the reduction in cerebral blood flow caused by infection. Also, LOV did not prevent the increased number of CD3+ cells and eNOS levels in the -infected brain. No alterations were observed on VCAM-1 and MCP-1 expressions, neither caused by infection nor LOV treatment. However, LOV prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with . These results suggest an anti-inflammatory activity of LOV, but more studies are needed to elucidate the role of LOV in CD acute infection.
PubMed: 38785783
DOI: 10.3390/biology13050301 -
Journal of the American Heart... Jun 2024Coronary microvascular function and hemodynamics may play a role in coronary circulation and myocardial remodeling in patients with aortic stenosis (AS). We aimed to...
BACKGROUND
Coronary microvascular function and hemodynamics may play a role in coronary circulation and myocardial remodeling in patients with aortic stenosis (AS). We aimed to evaluate the relationship between myocardial blood flow and myocardial function in patients with AS, no AS, and aortic valve sclerosis.
METHODS AND RESULTS
We included consecutive patients who had resting transthoracic echocardiography and clinically indicated positron emission tomography myocardial perfusion imaging to capture their left ventricular ejection fraction, global longitudinal strain (GLS), and myocardial flow reserve (MFR). The primary outcome was major adverse cardiovascular event (all-cause mortality, myocardial infarction, or late revascularization). There were 2778 patients (208 with aortic sclerosis, 39 with prosthetic aortic valve, 2406 with no AS, and 54, 49, and 22 with mild, moderate, and severe AS, respectively). Increasing AS severity was associated with impaired MFR (<0.001) and GLS (<0.001), even when perfusion was normal. Statistically significant associations were noted between MFR and GLS, MFR and left ventricular ejection fraction, and MFR and left ventricular ejection fraction reserve. After a median follow-up of 349 (interquartile range, 116-662) days, 4 (7.4%), 5 (10.2%), and 6 (27.3%) patients experienced a major adverse cardiovascular event in the mild, moderate, and severe AS groups, respectively. In a matched-control analysis, patients with mild-to-moderate AS had higher rates of impaired MFR (52.9% versus 39.9%; =0.048) and major adverse cardiovascular event (11.8% versus 3.0%; =0.002).
CONCLUSIONS
Despite lack of ischemia, as severity of AS increased, MFR decreased and GLS worsened, reflecting worse coronary microvascular health and myocardial remodeling. Positron emission tomography-derived MFR showed a significant independent correlation with left ventricular ejection fraction and GLS. Patients with prosthetic aortic valve showed a high prevalence of impaired MFR.
Topics: Humans; Aortic Valve Stenosis; Female; Male; Ventricular Remodeling; Aged; Ventricular Function, Left; Myocardial Perfusion Imaging; Fractional Flow Reserve, Myocardial; Stroke Volume; Microcirculation; Coronary Circulation; Echocardiography; Severity of Illness Index; Aged, 80 and over; Middle Aged; Retrospective Studies; Aortic Valve
PubMed: 38780160
DOI: 10.1161/JAHA.123.033447 -
American Heart Journal Plus :... Jun 2024Peripheral artery disease (PAD) is a highly prevalent disorder with a high risk of mortality and amputation despite the introduction of novel medical and procedural...
Peripheral artery disease (PAD) is a highly prevalent disorder with a high risk of mortality and amputation despite the introduction of novel medical and procedural treatments. Microvascular disease (MVD) is common among patients with PAD, and despite the established role as a predictor of amputations and mortality, MVD is not routinely assessed as part of current standard practice. Recent pre-clinical and clinical perfusion and molecular imaging studies have confirmed the important role of MVD in the pathogenesis and outcomes of PAD. The recent advancements in the imaging of the peripheral microcirculation could lead to a better understanding of the pathophysiology of PAD, and result in improved risk stratification, and our evaluation of response to therapies. In this review, we will discuss the current understanding of the anatomy and physiology of peripheral microcirculation, and the role of imaging for assessment of perfusion in PAD, and the latest advancements in molecular imaging. By highlighting the latest advancements in multi-modality imaging of the peripheral microcirculation, we aim to underscore the most promising imaging approaches and highlight potential research opportunities, with the goal of translating these approaches for improved and personalized management of PAD in the future.
PubMed: 38779485
DOI: 10.1016/j.ahjo.2024.100400 -
Heliyon May 2024According to the Standard of Chinese Medicinal Materials of Shaanxi Province (2015 edition), is the dried stems and leaves of , which could activate blood and dispell...
Comparative pharmacokinetic study on phenolic acids and flavonoids in normal and microcirculation dysfunction rats plasma by UPLC-TQ/MS/MS after oral administration of stem-leaf extracts.
According to the Standard of Chinese Medicinal Materials of Shaanxi Province (2015 edition), is the dried stems and leaves of , which could activate blood and dispell blood stasis, clear the mind and remove annoyance. In this study, the dynamic absorption changes of phenolic acids (FS) and phenolic acids-flavonoids (FT) in rats after oral administration were studied by UPLC-TQ/MS/MS, to elucidate the pharmacokinetics of seven major bioactive components of the stem-leaf of . The results showed that the pharmacokinetic parameters of FS and FT were significantly different in normal rats and model rats. Compared with the control group, after injecting 10 % polymer dextran 500 into the tail vein to establish a model of microcirculation disturbance, the of caffeic acid decreased. The of rosmarinic acid and lithospermic acid increased. Danshensu showed a decrease in , accompanied by an increase in both and . The of lithospermic acid was also increased. These results indicated that microcirculation disturbance could decrease the absorption of caffeic acid while increasing the absorption of danshensu, rosmarinic acid and lithospermic acid. After oral administration of FT, the of danshensu and the of caffeic acid were increased significantly, suggesting that the presence of flavonoids may promote the absorption and exposure of phenolic acids . This study provides a reference for the elucidation of the substances and the mechanisms of action of FS and FT from the stem-leaf of .
PubMed: 38778933
DOI: 10.1016/j.heliyon.2024.e30910 -
Chinese Medicine May 2024The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke....
BACKGROUND
The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved.
METHODS
Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamide-induced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels.
RESULTS
AGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endothelium-dependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP.
CONCLUSIONS
AGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulating the expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators.
PubMed: 38778375
DOI: 10.1186/s13020-024-00945-7 -
Frontiers in Endocrinology 2024The aim of this substudy (Eudra CT No:2019-001997-27)was to assess ATB availability in patients with infected diabetic foot ulcers(IDFUs)in the context of...
Does PAD and microcirculation status impact the tissue availability of intravenously administered antibiotics in patients with infected diabetic foot? Results of the DFIATIM substudy.
AIMS/HYPOTHESIS
The aim of this substudy (Eudra CT No:2019-001997-27)was to assess ATB availability in patients with infected diabetic foot ulcers(IDFUs)in the context of microcirculation and macrocirculation status.
METHODS
For this substudy, we enrolled 23 patients with IDFU. Patients were treated with boluses of amoxicillin/clavulanic acid(AMC)(12patients) or ceftazidime(CTZ)(11patients). After induction of a steady ATB state, microdialysis was performed near the IDFU. Tissue fluid samples from the foot and blood samples from peripheral blood were taken within 6 hours. ATB efficacy was the maximum serum and tissue ATB concentrations(C and C)and the percentage of time the unbound drug tissue concentration exceeds the minimum inhibitory concentration (MIC)(≥100% and ≥50%/60% fT>MIC). Vascular status was assessed by triplex ultrasound, ankle-brachial and toe-brachial index tests, occlusive plethysmography comprising two arterial flow phases, and transcutaneous oxygen pressure(TcPO).
RESULTS
Following bolus administration, the C of AMC was 91.8 ± 52.5 μgmL and the C of AMC was 7.25 ± 4.5 μgmL(<0.001). The C for CTZ was 186.8 ± 44.1 μgmL and the C of CTZ was 18.6 ± 7.4 μgmL(<0.0001). Additionally, 67% of patients treated with AMC and 55% of those treated with CTZ achieved tissue fT>MIC levels exceeding 50% and 60%, respectively. We observed positive correlations between both C and AUC and arterial flow. Specifically, the correlation coefficient for the first phase was 0.42; (=0.045), and for the second phase, it was =0.55(=0.01)and =0.5(=0.021).
CONCLUSIONS
Bactericidal activity proved satisfactory in only half to two-thirds of patients with IDFUs, an outcome that appears to correlate primarily with arterial flow.
Topics: Humans; Diabetic Foot; Microcirculation; Male; Female; Anti-Bacterial Agents; Middle Aged; Aged; Administration, Intravenous
PubMed: 38774229
DOI: 10.3389/fendo.2024.1326179