bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Distribution of Adrenergic Constrictor Responses Contributes to Skeletal Muscle Perfusion Abnormalities in Metabolic Syndrome
Authors: Lemaster Kent , Jackson Dwayne , Welsh Donald , Brooks Steven , Chantler Paul , Frisbee Jefferson 
Published: November 2023

Although studies have suggested elevations in adrenergic traffic, signaling and vascular responses with development of metabolic syndrome in obese Zucker rats (OZR), the moderate hypertension and modest impact on organ blood flow in OZR questions the multi‐scale validity of these data. To better understand the role of adrenergic function in contributing to vascular reactivity in OZR, we utilized a multi‐scale approach to investigate pressure responses, skeletal muscle blood flow and vascular reactivity in OZR following adrenergic challenge. For OZR under in vivo conditions, adrenergic challenge resulted increased pressor responses vs. LZR that were mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted hyperemic responses to elevated metabolic demand, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL as well. Within in situ cremaster muscle, proximal resistance arterioles of OZR exhibited a more heterogeneous constrictor response to adrenergic challenge, biased toward hyperresponsiveness, as compared to that in LZR. This increasingly heterogeneous pattern was mirrored in ex vivo resistance arterioles as well, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. These results support observations of the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity with development of metabolic syndrome that is presently of unclear purpose.Support or Funding InformationNational Institutes of Health and American Heart Association
Effect of aging on vascular smooth muscle contractility in skeletal muscle resistance arteries
Authors: Woodman Christopher , Seawright John , Shin Song Yi , Trache Andreea 
Published: November 2023

ObjectiveWe tested the hypothesis that vascular smooth muscle contractility declines with age in skeletal muscle resistance arteries.MethodsSoleus muscle feed arteries (SFA) from young (4 mo) and old (24 mo) Fischer 344 rats were cannulated with glass micropipettes and pressurized to 90 cmH2O for 1 h. To isolate the role of vascular smooth muscle, SFA were denuded (endothelium removed) by passing 5 ml of air through the lumen of the artery. At the end of the 1 h equilibration period, contractile responses were assessed using increasing whole log doses of norepinephrine (NE; 10−9–10−4 M), angiotensin II (Ang II; 10−11–10−7 M), and phenylephrine (PE; 10−9–10−4 M).ResultsVasoconstrictor responses NE, Ang II, and PE were significantly impaired in endothelium intact old SFA compared to young SFA. In contrast, vasoconstrictor responses to NE, Ang II, and PE were similar in young and old denuded SFA.ConclusionThese results indicate that the contractile properties of vascular smooth muscle cells are preserved with age and that impaired constrictor responses are manifest only when the endothelium is intact.Support or Funding InformationResearch support: AHA grant 0765043Y, AHA grant 4150031, The National Space Biomedical Research Institute through NCC 9–58 and a Sydney and J.L. Huffines Institute of Sports Medicine Graduate Student Research Grant.
Presence of Hysteresis in the Cerebral Pressure‐Flow Relationship During Repeated Squat‐Stand Maneuvers in Humans
Authors: Brassard Patrice , Ferland‐Dutil Hélène , Smirl Jonathan David , Paquette Myriam , Le Blanc Olivier , Malenfant Simon , Ainslie Philip Neil 
Published: November 2023

In humans, the cerebrovasculature is more efficient at compensating for transient hypertension compared with transient hypotension – a phenomenon called hysteresis. To date, however, these asymmetrical responses of cerebral blood flow (CBF) in response to changes in blood pressure have been reported using cyclic inflation and deflation of thigh cuffs in patients with head injury or via pharmacological interventions in healthy participants. Whether this phenomenon exists during non‐pharmacologically and physiologically‐induced transient hypertension and hypotension is unknown. In this study, we compared the relative change in CBF, as indexed by mean velocity in the middle cerebral artery (MCAvmean; transcranial Doppler), per relative change in mean arterial pressure (MAP; finger photoplethysmography) (%MCAvmean/%MAP) during transient hypertension and hypotension. These changes in MAP were reliability and repetitively induced during 5 minutes of repeated squat‐stand maneuvers performed at 0.05 Hz (10‐second squat–10‐second stand) and 0.10 Hz (5‐second squat–5‐second stand) in 64 healthy participants (Age [(mean±SD)] 32±14 yrs). These large oscillations in MAP (~25–30 mmHg) are transmitted to the cerebrovasculature when executed at frequencies within the high‐pass filter buffering range (<0.20 Hz). However, the results revealed the %MCAvmean/%MAP was attenuated by 26% ([median (range)]: 0.96 (−3.79–5.22) vs. 1.29 (−1.12–8.55) %/%; p=0.02] and 47% [0.92 (−2.93–3.26) vs. 1.74 (−0.29–9.38) %/%; p=0.0001] during transient hypertension compared to transient hypotension performed at 0.05 and 0.10 Hz, respectively. These findings suggest that the human cerebrovascular function is better adapted to compensate for physiologically relevant transient hypertension than transient hypotension.Support or Funding InformationThis research was supported via the Ministère de l'Education, du Loisir et du Sport du Quebec (PB), the Foundation of the Institut universitaire de cardiologie et de pneumologie de Quebec (PB), and an NSERC Discovery grant (PNA). PB was a Junior 1 Research Scholar of the Fonds de recherche du Québec – Santé.JDS was supported via an NSERC PGS‐D2 Fellowship and the Killam Pre‐Doctoral Fellowship. MP was supported via a scholarship from CIHR.
High Fat Feeding Reduces Cerebral Artery Transient Receptor Potential Channel Vanilloid 4 (TRPV4) Expression In A Mineralocorticoid Receptor‐Dependent Manner
Authors: Dorrance Anne McLaren , Diaz‐Otero Janice , Pires Paulo W , Jackson William F 
Published: November 2023

Overweight/obese patients are at an increased risk of developing cognitive impairment associated with chronic cerebral hypoperfusion. We have developed an overweight rat model that exhibits impaired cerebral artery endothelial function and cognitive decline. The mechanisms responsible for the impaired cerebral artery dilation have not been determined. Recent studies from our laboratory have identified the transient receptor potential channel (TRP) vanilloid 4 (TRPV4) as a key regulator of cerebral artery endothelium‐dependent dilation. We therefore hypothesized that TRPV4 mRNA expression would be reduced in cerebral arteries from overweight rats. Cerebral arteries were collected from overweight rats fed a high fat (HF) diet for 17 weeks from 3 weeks of age; these were compared to arteries from control chow fed rats (n=5 in each group). qRT‐PCR with TAQMAN primers was used to assess TRPV4 expression, TRPV3 and TRPA1 expression were also assessed. HF feeding specifically reduced TRPV4 mRNA expression (fold change from control = 0.58±0.11; p<0.01), while it had no effect on TRPV3 (fold change from control = 1.144±0.28; p=0.6) or TRPA1 (fold change from control = 1.08±0.2; p=0.7) mRNA expression. Circulating levels of aldosterone are increased in the overweight population, to test if this plays a role in the reduced TRPV4 expression observed with HF feeding we treated rats with the mineralocorticoid receptor (MR) antagonist canrenoic acid (CAN 20mg/kg/day n=3) for the duration of the HF feeding, these were compared to placebo treated HF fed rats (n=5). MR antagonism increased the mRNA expression of TRPV4 (fold change from HF placebo treated = 2.012±0.24; p<0.01). CAN treatment also increased the expression of doublecortin, a marker of new and immature neurons (fold change from HF placebo treated = 2.184±0.37; p<0.01) and synaptophysin a marker of synapse formation (fold change from HF placebo treated = 2.90±1.05; p<0.01). Taken together these studies suggest the MR antagonism improves expression of TRPV4, a key regulator of cerebral artery dilation. Augmented expression of TRPV4 may improve cerebral perfusion, and may reduce the cognitive decline observed in the overweight population.Support or Funding InformationSupported by 5P01HL070687‐12.
Cerebrovascular Reactivity in Atrial Fibrillation
Authors: Fisher James P , Braz Igor Dutra , Lucas Samuel J E , Edwards Louisa , van Lieshout Johannes J , Lip Gregory Y H 
Published: November 2023

Atrial fibrillation is associated with substantial risk of severe stroke, cognitive decline and dementia. Elevated plasma biomarkers of vascular damage/dysfunction and reduced conduit (brachial) artery function have been reported in atrial fibrillation. We sought to test the hypothesis that patients with atrial fibrillation have a reduced cerebrovascular reactivity to carbon dioxide (CO2) in comparison with age‐matched, healthy control and hypertensive participants.Middle cerebral artery flow velocity was measured at rest and during step‐wise changes in partial pressure of end‐tidal CO2 (PETCO2) in 14 patients with atrial fibrillation (median [IQR]; 66.5 [59.5–69.3] yr, 3 women), 8 patients with hypertension (65.5 [63.5–71.5] yr, 4 women) and 10 healthy control participants (67.5 [66–70] yr, 4 women). Incremental hypercapnia was delivered via the open circuit steady‐state method, with stages of 4% and 7% CO2. Incremental hypocapnia was comprised of two 2‐min stages of voluntary hyperventilation to reduce PETCO2 in an equal but opposite direction to that observed during hypercapnia. Cerebrovascular reactivity was calculated as the change in middle cerebral artery mean flow velocity, per mmHg change in PETCO2.Resting middle cerebral artery mean flow velocity tended to be lower in patients with atrial fibrillation (mean [SD]; 54.4 [14.5] cm/s) and hypertension (54.6 [13.0] cm/s), when compared to healthy controls (65.9 [14.4] cm/s) (P=0.127). Hypercapnic cerebrovascular reactivity was ≈50% lower in patients with atrial fibrillation (median [IQR]; 1.7 [1.5–2.4] cm/s/mmHg) and ≈22% lower in patients with hypertension (2.7 [2.2–3.1] cm/s/mmHg), compared to healthy controls (3.4 [2.8–3.8] cm/s/mmHg) (P<0.05). Hypocapnic cerebrovascular reactivity was not significantly different between groups (P>0.05).In summary, atrial fibrillation patients exhibit blunted hypercapnic cerebrovascular reactivity when compared to healthy control participants. Such impairments in cerebrovascular reactivity may contribute to the well‐established increased risk of cerebrovascular events in this patient group.Support or Funding InformationFunded by BHF project grant PG/15/45/31579.
Elevating CXCR7 improves angiogenic function of EPCs via Akt/GSK‐3β/Fyn‐mediated Nrf2 activation in diabetic limb ischemia
Authors: Dai Xiaozhen , Zeng Jun , Chen Jing , Cai Lu , Tan Yi 
Published: November 2023

RationalEndothelial progenitor cells (EPCs) respond to SDF‐1 through receptors CXCR7 and CXCR4. Whether SDF‐1 receptors involves in diabetes induced EPCs dysfunction remains unknown.ObjectiveTo determine the role of SDF‐1 receptors in diabetic EPCs dysfunction.Methods and ResultsCXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up‐regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low‐density lipoprotein (ox‐LDL) and high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox‐LDL and HG were markedly reduced by SDF‐1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7‐EPCs) but not in EPCs transduced with control lentivirus (Null‐EPCs). Most importantly, CXCR7‐EPCs were superior to Null‐EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox‐LDL and HG inhibited Akt and GSK‐3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, resulting in inhibiting Nrf2 downstream target genes HO‐1, NQO‐1 and catalase, and a corresponding increase in EPC oxidative stress. This destructive cascade could be blocked by SDF‐1 treatment in CXCR7‐EPCs. Furthermore, inhibition of PI3K/Akt prevented SDF‐1/CXCR7‐mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF‐1/CXCR7 on EPC function in vitro and in vivo.ConclusionsElevated expression of CXCR7 enhances EPC resistance to diabetes‐induced oxidative damage and improves therapeutic efficacy of EPCs for treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by the Akt/GSK‐3β/Fyn pathway producing increased activity of Nrf2.Support or Funding InformationThis study was supported in part by a Junior Faculty Award (1–13‐JF‐53) from American Diabetes Association, an Innovative Grant (1‐INO‐2014‐122‐A‐N) from Juvenile Diabetes Research Foundation, NSFC projects (81573435, 81200917, 81200239, 81370917).
Chloroquine Attenuates Endothelium‐dependent Relaxation in Mouse Coronary Artery
Authors: Zhang Qian , Wang Jian , Makino Ayako 
Published: November 2023

Chloroquine (CQ) is widely used as an antimalarial drug and it is also effective in treating the symptoms of lupus. It has been reported that CQ exhibits cardiotoxicity and has an adverse effect on nerve system by overdose or prolonged treatment of CQ. However, little is known about the effect of CQ on cardiovascular system. This study was designed to examine the effect of CQ on vascular relaxation in coronary artery. Third‐ or fourth‐order small coronary arteries were dissected from mice and the rings were mounted in a wire myograph with 20μm wires. Endothelium‐dependent relaxation was conducted by ACh administration in a dose‐dependent manner. Endothelium‐derived hyperpolarization (EDH)‐dependent relaxation was observed by inhibition of NO (via L‐NAME, 100 μmol/L) and prostacyclin (via indomethacin, 10 μmol/L) during ACh‐induced relaxation. A cocktail of apamin (100 nmol/L) and TRAM34 (10 μmol/L) was used to inhibits EDH‐dependent relaxation. CQ (10 μmol/L) was treated for 30 min before vascular constriction by PGF2α. CQ significantly inhibited endothelium‐dependent relaxation compared to the control (vehicle treatment), whereas CQ had no effect on sodium nitroprusside‐induced relaxation (endothelium‐independent relaxation). Interestingly, EDH‐dependent relaxation was markedly enhanced by the pretreatment of CQ compared to the vehicle pretreatment. ACh‐induced relaxation was diminished in the presence of L‐NAME, indomethacin, apamin, and TRAM34. These data suggest that CQ might inhibit endothelium‐dependent relaxation via, at least in part, the decrease in NO production and/or NO bioavailability in endothelial cells, but not due to altering EDH‐dependent relaxation.Support or Funding InformationNIH/HL115578
Endothelial Specific Molecule 1 (Esm‐1) Inhibits Macrophage Infiltration in a Mouse Model of Goodpasture's Syndrome
Authors: Zheng Xiaoyi , Higdon Lauren , Maltzman Jonathan , Bhalla Vivek 
Published: November 2023

Goodpasture's syndrome is an autoimmune disorder caused by pathogenic antibodies to kidney and lung basement membranes causing acute kidney and lung injury, respectively. We modeled this syndrome by treatment with anti‐GBM (Glomerular Basement Membrane) antibodies leading to glomerular and tubulointerstitial inflammation in mice. Endothelial Specific Molecule1 (Esm‐1)/endocan is a secreted glycoprotein highly expressed in kidney glomeruli and lung endothelium and is proposed to disrupt molecular interactions that mediate leukocyte infiltration and anti‐GBM nephritis. To discover the in vivo functional role of Esm‐1 in leukocyte infiltration in anti‐GBM mice, we delivered Esm‐1 plasmid for stable integration to anti‐GBM mice and controls by hydrodynamic tail vein injection. We quantified kidney leukocyte infiltration by separating glomerular and tubulointerstitial compartments, dissociating into single cells, and measuring leukocyte subtypes by flow cytometry. In contrast to i.p. administration of recombinant Esm‐1 which has an abbreviated half‐life in mouse serum (less than 2 hours), we induced ~12‐fold increase in circulating Esm‐1 that persists for 2 weeks compared to control injected mice, by hydrodynamic injection of an Esm‐1‐expressing plasmid (11242 +/− 3324 vs. 958 +/− 188 pg/mL, p<0.05, N=3–5/group). We demonstrate that by flow cytometry, anti‐GBM mice show significantly increased glomerular (3.4 +/− 0.47% vs. 1.1 +/− 0.33%, p < 0.01, N=8/group) and tubulointerstitial (1.4 +/− 0.14% vs. 0.1+/− 0.032%, p < 0.01, N=8/group) CD45+ leukocytes seven days post treatment with anti‐GBM antisera. The increase in CD45+ cells includes increased glomerular (3.4 +/− 0.47% vs. 1.1 +/− 0.33%, p < 0.01) and tubular (1.2 +/− 0.14% vs. 0.1+/− 0.025%, p < 0.01) macrophages. By increasing circulating Esm‐1, we significantly decreased macrophage infiltration in the tubulointerstitium (4.2 ± 1.3% vs. 1.6 ± 0.4%, P < 0.01), but did not influence glomerular macrophage infiltration (2.3 ± 1.2% vs. 1.5 ± 0.2%, P = 0.13). Furthermore, Esm‐1 does not alter kidney neutrophils (glomerular: 0.013 ± 0.007% vs. 0.010 ± 0.006%, p = 0.61; tubulointerstitial: 0.19 ± 0.02% vs. 0.27 ± 0.07%, p = 0.085) or lymphocytes(glomerular: 1.7 ± 0.8% vs. 1.9 ± 0.9%, p = 0.89; tubulointerstitial: 1.9 ± 0.70% vs. 2.2 ± 0.71%, p = 0.64). We also found that inhibition of macrophage infiltration was dependent on glycosylation of Esm‐1. Furthermore, we have generated Esm‐1 knockout mice for complementary studies. We conclude that in contrast to deletion of the inflammatory mediator ICAM‐1, Esm‐1 inhibits inflammation in a tissue and cell‐specific manner. Esm‐1 provides a natural biologic inhibitor of inflammation, and based on its expression pattern, may be a key therapeutic target in pulmonary‐renal syndromes.Support or Funding Information1. Larry L. Hillblom Foundation2. Holmgren Family3. NIDDK
Racial Differences in CRP Receptor and Influence on eNOS Bioactivity and NO Production in Endothelial Cells
Authors: Aldokhayyil Maitha , Ling Chenyi , Cook Marc , Grimm Heather , Brown Michael D 
Published: November 2023

BackgroundC‐reactive protein (CRP) is an independent biomarker of inflammation and cardiovascular disease (CVD). CRP interacts directly with endothelial cells. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity and decreases nitric oxide (NO) production. Race/ethnicity is significantly associated with CRP and CVD risks. Thus, the purpose of this study was to assess the racial differences concerning the CRP‐induced biological effects in endothelial cells.MethodsHuman umbilical vein endothelial cells (HUVECs) from four African American (AA) donors and four Caucasian (CA) donors were cultured and incubated with CRP to assess its effects on eNOS bioactivity and NO production measured in cell culture media.ResultsAA and CA HUVECs responded differently to CRP incubation. We report significant increase in FcγRIIB receptor expression under both basal and CRP incubation conditions in AA HUVECs cells (~2‐fold difference, p < .01, Fig 1). This may contribute to the racial differences of CRP‐induced effects on endothelial cells with AA HUVECs showing greater impairment of eNOS expression and bioactivity (~2‐fold decrease, p < .01, Fig 2) and reduced NO production basally (CA: 11.09 ± 1.002 AA: 8.254 ± 0.5285 μmol/L; mean ± SEM, p=0.04). CRP incubation reduced NO production significantly in both AA and CA (CA: 3.947 ± 0.7360 AA: 2.756 ± 0.4368 μmol/L, p <.0001, Fig 3).ConclusionA better understanding of the racial differences in endothelial function will help to improve CVD prevention and treatment. The results suggest that the racial differences in CRP‐induced pro‐inflammatory and pro‐atherogenic biological effects on endothelial cells may be partially due to the differential expression of FcγRIIB receptor which may contribute to the disproportionate CVD rates in AA.Support or Funding InformationACSM Doctoral Student Research Grant to Chenyi Ling
Potential sympathetic activation in response to a training macrocycle is associated sport injuries incidence in competitive sprint swimmers
Authors: Oliveira‐Junior Silvio A , Lima‐Borges Dayanne S , Vanderlei Luiz Carlos M , Barbosa Fernando S S , Okoshi Marina P , Okoshi Katashi , Martinez Paula F 
Published: November 2023

Although overtraining has been associated with disturbed cardiac autonomic modulation and sport injuries incidence, these issues are poorly understood in swimmers. This study analyzed heart rate variability (HRV), stress/recovery relationship, and sport injuries incidence during a training periodization of teenager swimmers of different modalities.MethodsThirty teenager swimmers (12 until 17 years‐old) were divided in two groups, according swimming modality: Sprint (n=17) and Endurance (n=13). Subjects were evaluated during a training periodization with twenty weeks of duration, scheduled on three stages: general period (GP, 8 weeks), technical preparation (TP, 8 weeks), and competitive period (CP, 4 weeks). To prospectively analyze HRV, time and frequency domain measures were obtained at the end of each training period. Besides sport injuries incidence, stress/recovery states in athletes were continuously analyzed with the Recovery‐Stress‐Questionnaire of Athletes. All proceedings were developed in initial moment and in the end of each periodization step. HRV results were analyzed by ANOVA and Bonferroni's test; sports injuries incidence was analyzed by Student t‐test.ResultsSprint showed progressive reduction in HRV, supported by significant reductions in multiple time‐domain results (SDNN, RMSSD, and pNN50) between GP and CP. Additionally, regarding responses in the frequency domain within Sprint group, participants have also presented increased values of low frequency (GP, 48.5±4.3; CP, 58.5±4.0 nu; p=0.022), and reduced high frequency (GP, 51.4±4.3; CP, 40.6±4.0 nu; p=0.012) in competitive period compared to general preparation period; Endurance exhibited unchanged HRV results during all training macrocycle. Stress/recovery monitoring was affected by the swimming training periodization in both swimming groups (p<0.05); both differences between recovery and stress scales levels within global and sport specific contexts have increased at the end of the TP and CP, respectively, compared to general preparation period. Moreover, sprint swimmers showed higher measures of incidence of sport injuries than endurance athletes (Sprint, 0.0214±0.0068; Endurance, 0.0136±0.0050 cases/1000 hours; p<0.05).ConclusionSprint training was associated with probable activation of the sympathetic nervous system and decreased heart rate variability, besides higher incidence of sport injuries, in comparison to endurance swimming during a training macrocycle.Support or Funding InformationFinancial support: CAPES; FUNDECT/MS