bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Aerobic Fitness, Contraceptive Use, and Height on Cardiac Augmentation Index in Young Healthy Females
Authors: Smith Michael , Devor Steven 
Published: November 2023

PURPOSEWhile female hormones and high levels of aerobic fitness may offer a protective advantage against arterial stiffness in young women, short stature may negate this benefit. Our goals were to identify the key determinates of augmentation index (AIx) and investigate the influence that cyclic fluctuations of estradiol and progesterone have on ventricular‐vascular coupling in young healthy women.METHODWe assessed the relationship between maximal aerobic capacity (VO2max) and AIx standardized to 75 beats per minute (AIx@75 BPM). Twenty two nulliparous women taking either Loestrin (n=5), Ortho‐cyclen (n=5), or no contraceptive (n=12) underwent graded exercise testing and applanation tonometry of the radial artery to measure VO2max and AIx, respectively, during low hormonal status (±48h menses). Subsequently, AIx@75 BPM was measured at days 7, 14, and 21 post‐menses. Saliva was collected for analysis of estradiol and progesterone at all 4 time points.RESULTSIn all subjects, there was a statistical difference in AIx between mid‐follicular and early luteal phases (P <0.01), and between late luteal and early follicular phases (P<0.05). AIx was strongly and negatively associated with relative aerobic fitness (R2=.42, P<0.0001), and an additional 17% of this relationship was explained when corrected for height (R2=.69, P<0.0001). 14% of the variation in AIx@75 BPM was further explained by no contraceptive use, body composition, and peripheral diastolic blood pressure.CONCLUSIONSAIx fluctuates inversely with estradiol concentrations throughout the menstrual cycle. High aerobic capacity is associated with favorable AIx and may offer a mechanism that protects ventricular‐vascular coupling efficiency from deleterious variables such as short stature, age, and impedance mismatch. These results underscore the importance of regular exercise for women for enhanced heart and vascular health, especially as they approach menopause.
Altered Ca2+ Dynamics and Vascular Function During Low‐flow Induced Vascular Remodeling
Authors: Weber David S , Choi Chung‐Sik , Bayazid Leith , Glosemeyer Katherine , Taylor Mark S 
Published: November 2023

In light of the widely recognized fact that the integrated endothelial cell response to shear stress is pivotal in the control of VSMC‐mediated wall remodeling, it is striking that the underlying Ca2+ signaling remains poorly understood. We hypothesized that low flow and sustained oscillatory shear stress results in decreased number, size and range of functional Ca2+ events in endothelial cells facilitating changes in vascular function and neointima formation. To test this, we used a partial carotid ligation model in C57BL/6J mice to induce chronic in vivo low flow and oscillatory shear stress. After 14 days of ligation, both control and partially ligated carotid arteries were harvested from each animal. Partial ligation resulted in substantial vascular remodeling (intima/media ratio of .42±.13), while no remodeling occurred in non‐ligated contralateral control carotids. To measure Ca2+ dynamics, carotid artery segments were opened longitudinally and pinned, luminal‐side‐up on Sylgard blocks with tungsten micropins. Arteries were loaded with fluo‐4 AM and Ca2+‐dependent fluorescence measured with a spinning‐disk laser confocal microscope. Partial ligation led to basal reductions in distinct signaling sites as well as the magnitude and spread of endothelial Ca2+ events in the endothelium. Using a modified parallel‐plate flow chamber to induce acute changes in shear stress, our studies demonstrated that a chronic long‐term decrease in flow leads to decreased Ca2+signaling sites and a shift from wide‐scale predominant waves to frequent localized Ca2+ transients along the intima. Acetylcholine (1 uM) produced sustained Ca2+ events in control endothelium but these were reduced to small periodic transients in partially ligated carotids. This pattern corresponded with impaired acetylcholine‐mediated relaxation as determined using myography (Control 60±10% vs Partial ligation 25±7%) while maximal relaxation in response to sodium nitroprusside was similar. Phenylephrine‐induced vasoconstriction was enhanced 2‐fold in partially ligated carotid arteries compared to control while KCl induced contraction following partial ligation was decreased 50%. Our findings indicate that chronic low flow in vivo in the absence of other confounding factors leads to significant neointima formation and changes in Ca2+ dynamic patterning. Current studies are on‐going to identify unique pattern changes in endothelial Ca2+ events associated with altered vascular function and investigate the subsequent changes in Ca2+ mediated endothelial signaling underlying the development of vascular pathology.Support or Funding InformationNIH HL084159 (DSW) and HL085887 (MST)
Altered vascular endothelial control of facial skin blood flow in rosacea
Authors: Metzler‐Wilson Kristen , Kube Megan , Mann Sarah , Demidova Olga , Sammons Dawn L , Wilson Thad E 
Published: November 2023

Sympathetic outflow to the face may be augmented in rosacea, a disorder which clinically presents with flushing (Metzler‐Wilson & Toma, et al, J Neurophysiol, 2015). To determine whether regulatory mechanisms of skin blood flow (SkBF) are altered by these chronic outflow differences or associated inflammatory mediators, SkBF oscillations were assessed in 9 otherwise healthy subjects with rosacea and age‐sex matched controls during baseline and local heat stress (42°C, 30 min). Local heating is classified as a flushing trigger in rosacea and induces cutaneous vasodilation with an initial axon reflex‐mediated peak and a second nitric oxide‐mediated peak. We hypothesized that compared to controls, individuals with rosacea would demonstrate greater changes in spectral power in the vascular endothelial (very‐low frequency (VLF); 0.009–0.02 Hz) and sympathetic (low frequency (LF); 0.02–0.06 Hz) frequency ranges during heating of typically rosacea‐affected (forehead, cheek) but not rosacea‐unaffected (forearm, palm) skin areas. SkBF (laser‐Doppler flowmetry) was measured and changes in SkBF spectral power (fast Fourier transform) in VLF and LF ranges from baseline to heating were determined at each skin site. Individuals with rosacea had significantly greater changes in VLF SkBF spectral power in cheek (0.024±0.003 vs. 0.006±0.002 au; p=0.03) and forehead (0.030±0.003 vs. 0.011±0.001 au; p=0.04) but not forearm (0.015±0.002 vs. 0.013±0.001 au; p=0.76) or palm (−0.019±0.006 vs. −0.041±0.005 au, rosacea and control, respectively; p=0.38) sites. There were no significant differences in the change in LF SkBF spectral power between groups (cheek p=0.29, forehead p=0.35, forearm p=0.69, palm p=0.80). These data indicate that during local heat stress, individuals with rosacea have altered vascular endothelial control of facial SkBF. These vascular endothelial differences may be due to chronic neuroinflammatory processes.Support or Funding InformationNational Rosacea Society
Downregulation of the Nuclear Factor (Erythroid‐Derived 2)‐Like 2 (NRF2) Antioxidant Defense System Contributes to Endothelial Dysfunction and Microvascular Rarefaction with Elevated Dietary Salt Intake
Authors: Lombard Julian H. , Kautenburg Katie E. , Priestley Jessica R. C. , McCord Joe M. , Greene Andrew S. , Geurts Aron M. 
Published: November 2023

A high salt diet leads to vascular oxidant stress, endothelial dysfunction, and microvascular rarefaction, which can be ameliorated by chronic infusion of a low dose of angiotensin II (ANG II) or angiotensin (1–7) [ANG(1–7]. The present study investigated the role of the NRF2 antioxidant defense system in mediating the protective effect of ANG II and ANG (1–7) to ameliorate endothelial dysfunction and microvascular rarefaction occurring with elevated dietary salt intake. In these experiments, short term (3 days) high salt diet (4% NaCl) eliminated endothelium‐dependent dilation to acetylcholine (ACh) in isolated middle cerebral arteries (MCA) and reduced microvessel density (assessed with rhodamine‐labeled GS1 lectin) in the cremaster muscle of Sprague‐Dawley (S‐D) parental strain rats. The NRF2 inducers Protandim and sulforaphane restored ACh‐induced dilation of MCA and increased microvessel density in S‐D rats fed HS diet for 2 weeks. Deletion mutation of the Nrf2 gene utilizing TALEN technology eliminated the protective effect of ANG II infusion and significantly reduced the protective effect of ANG (1–7) infusion to restore ACh‐induced dilation of the MCA. The Nrf2 (−/−) mutation also eliminated the ability of ANG II and ANG (1–7) to prevent microvascular rarefaction in HS fed rats. Protandim restored endothelium dependent dilation to ACh in MCA of HS fed wild type controls, but not MCA of HS‐fed Nrf2 (−/−) mutant rats. These findings indicate that down regulation of NRF2‐mediated antioxidant defenses due to salt‐induced suppression of the renin‐angiotensin system leads to vascular oxidant stress, endothelial dysfunction, and microvascular rarefaction; and suggest that dietary upregulation of the NRF2 antioxidant system may be a valuable therapeutic approach to ameliorate endothelial dysfunction with HS diet and in low renin forms of salt‐sensitive hypertension.Support or Funding InformationNIH #R‐01 HL65289‐12; #R56 HL65289‐13A1, and #R21 OD018309‐01
Effects of acute TUDCA administration on postprandial hyperglycemia and endothelial function
Authors: Walsh Lauren Kay , Restaino Robert , Manrique Camila , Padilla Jaume 
Published: November 2023

Previous studies have shown that postprandial hyperglycemia causes a transient impairment in endothelial function; however, the mechanisms remain largely unknown. Herein we tested the hypothesis that hyperglycemia‐induced endothelial dysfunction is attributed to endoplasmic reticulum (ER) stress. Specifically, we hypothesized that acute oral administration of tauroursodeoxycholic acid (TUDCA, 1500mg), a chemical chaperone known to alleviate ER stress, would prevent hyperglycemia‐induced endothelial dysfunction. In 10 young healthy subjects (five men, five women), brachial artery flow‐mediated dilation (FMD) was assessed at baseline, 1 hour, and 2 hours post oral administration of a 75g glucose load. Subjects were tested on two separate visits in a single‐blind randomized crossover design: after oral ingestion of TUDCA or placebo capsules. FMD was reduced during hyperglycemia under the placebo condition (baseline: 7.01± 1.00%, 1hr: 4.75± 0.68%, 2hr: 5.29± 0.55%) but not under the TUDCA condition (baseline: 5.62± 0.67%, 1hr: 5.43±0.84%, 2hr: 6.01±0.91%). These preliminary results suggest that hyperglycemia‐induced endothelial dysfunction can be mitigated with oral administration of TUDCA, thus supporting the hypothesis that ER stress may contribute to endothelial dysfunction during postprandial hyperglycemia.Support or Funding InformationSupport: NIH R21DK105368 (Jaume Padilla)
Decreased Systemic Microvascular Function May Contribute to Increased Cardiovascular Risk in Women with Asthma
Authors: Kapoor Karishma , Moore Linn E , Byers Bradley W , Stickland Michael K 
Published: November 2023

INTRODUCTIONIndividuals with asthma are at increased risk of developing cardiovascular disease (CVD), with the greatest risk being reported among asthmatic women. The mechanisms underlying differences in CVD risk between sexes are presently unknown. However, endothelial and microvascular dysfunction, and elevated arterial stiffness are early indicators of CVD development and have been shown to be predictive of adverse cardiovascular outcomes. The purpose of this study was to examine markers of vascular health and thus, CVD risk in men and women with asthma.METHODSThirteen male (27.9±6.3 years) and eleven female asthmatics (24.7±4.7 years), matched for BMI, were recruited for the study and screened for known cardiovascular conditions. Participants were required to fast and refrain from drinking alcohol, exercising, and using a bronchodilator for 12 hours prior to testing. Endothelial function was assessed by flow‐mediated dilation normalized to shear stress (FMD/SS). Microvascular function was evaluated as hyperemic blood flow (Velocity Time Integral, VTI; cm/s) and arterial stiffness as carotid and radial pulse wave velocity (PWV; m/s). All measurements were done in the supine position following 10 minutes of rest. Two‐tailed Student's t‐tests were used to for statistical comparison between males and females.RESULTSNo between‐group differences were seen in endothelial function (female: 0.054±0.009; male: 0.058±0.047, p=0.820), or arterial stiffness (7.8±1.5; 8.8±1.3 m/s, p=0.115). However, women had reduced microvascular function, evaluated as reactive hyperemic blood flow, in comparison to men (74.7±17.4; 96.7±28.2 cm/s, p=0.035).CONCLUSIONSAsthmatic women have reduced microvascular function compared to asthmatic men, which may be a contributing factor to the increased risk of CVD seen among women with asthma.Support or Funding InformationThe Lung Association, Alberta & North West Territories (NWT)
Development of a Novel Technique to Isolate and Characterize Mouse Podocytes
Authors: Kung Ling Hsuan , Wasti Ruby , Tibolla Annette , Gibson Glenn , Pullen Steven , MacDonnell Scott 
Published: November 2023

INTRODUCTIONPodocytes play a key role in the selective filter that underlies kidney function. The loss of mature podocytes is involved in chronic kidney disease progression. The mechanisms of podocyte injury, leading to proteinuria are still unclear due to lack of consistent and validated methods to study primary podocytes. In vitro system, glomerular outgrowth and human immortalized cell line (HIC) have their merits; however, these cells fail to express podocyte specific markers and variations in culture protocols challenge their utility. Hence, an isolation method is required to define potential mechanism involved in disease progression.METHODSMouse glomeruli were digested in Liberase (100 μg/ml, 40 min) followed by trypsin (0.075%, 20 min). Mixed cells were filtered (70μm) and a 15% BSA cushion was used to eliminate debris. Podocytes were then enriched using anti‐nephrin and magnetic beads via columns. Expression of selected genes was compared between glomerular (G), nephrin positive (N+) fraction, and HIC.RESULTSWhile podocyte selective markers were observed in the G fractions, significant expression can only be observed in N+. Podocyte specific genes are enriched in N+; ΔCT WT1 (N+ 3.6 vs. G 7.5), Podocin (N+ 0.8 vs. G 4.5), and TRPC6 (N+ 5.76 vs. G 12.4). Same genes also expressed higher in N+ than fully differentiated HIC; ΔCT WT1 (N+ 3.6 vs. HIC 12.2), podocin (N+ 1.9 vs. HIC 17.4), and TRPC6 (N+ 5.7 vs. HIC 16.6). Mesangial cell specific gene SerpinB7 was not observed in N+ (ΔCT14.8), but was expressed in HIC (ΔCT 8.8), confirmed the specificity of N+ cells.CONCLUSIONA method has been developed to isolate and enrich mouse podocytes. It provides utility to study podocytes from healthy and diseased kidneys to identify druggable targets and pathways. However, additional studies are required to profile the function of N+ and possibility for long term culture.Support or Funding InformationSupported by Cardio‐Metabolic Disease Research Department, Boehringer Ingelheim
Elucidating the Role of Arginases in Diabetic Nephropathy: Arginase 2‐dependent and ‐independent Effects
Authors: Awad Alaa S. , You Hanning , Gao Ting , Cooper Timothy K , Morris Sidney M 
Published: November 2023

Diabetes is the leading cause of end stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. As current therapies for progression of diabetic nephropathy are only moderately successful, identification of underlying mechanisms of disease process is essential in order to develop more effective therapies.We showed previously that treatment with an arginase inhibitor or genetic deficiency of the arginase 2 isozyme was protective against several key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all tested markers of diabetic nephropathy were dependent only on arginase 2 expression.The objective of this study was to identify features of diabetic nephropathy that are associated specifically with arginase 2 expression.The arginase inhibitor S‐(2‐boronoethyl)‐L‐cysteine or vehicle was continuously infused via minipump in male wild‐type and arginase 2‐deficient (Arg2−/−) mice for 12 weeks following induction of diabetes by streptozotocin injection.Our results demonstrate that elevated urinary albumin excretion rate and plasma urea levels, and decreased renal medullary blood flow, were associated almost completely and specifically with arginase 2 expression. Furthermore, diabetes‐dependent increases in renal fibronectin mRNA levels were largely dependent on arginase 2 expression, with no indication of any significant contribution by arginase 1.These findings indicate that arginase 2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF‐α mRNA levels occurred independently of arginase 2 expression but were almost entirely abolished by treatment with the arginase inhibitor, indicating that arginase 1 is required for increases in these markers of diabetic renal pathology.Support or Funding InformationThis study was supported by NIH Grants DK094930 and DK094930S1
ENaC activity in the collecting ducts of the STZ‐induced type 1 diabetic Dahl SS rats
Authors: Pavlov Tengis S. , Ilatovskaya Daria V. , Levchenko Vladislav , Brands Michael W. , Staruschenko Alexander 
Published: November 2023

The epithelial sodium channel (ENaC) is expressed in the aldosterone sensitive distal nephron where it performs sodium reabsorption from the lumen. Previous studies indicate that high glucose upregulates ENaC expression and activity in cultured cortical collecting duct cells. However, activity of this channel has never been studied in a rodent models of diabetes. Streptozotocin (STZ) treatment is a widely accepted approach to study type 1 diabetes (T1D). However, while Sprague Dawley rats or other salt‐resistant rodent models develop hyperglycemia and T1D after STZ treatment, they do not develop essential features of diabetic nephropathy (DN). To address this limitation, we induced T1D in the Dahl Salt‐Sensitive (SS) rat, which is a model of salt‐sensitive hypertension. We and others reported that 11–12 weeks of STZ‐induced diabetes is sufficient for the animals to develop hyperglycemia, polyuria, weight loss, microalbuminuria, nephrinuria and display renal histological lesions typical for patients with DN. T1D was induced in 6 week old male SS rats with a single i.p. injection of 75 mg/kg STZ. An insulin pellet was implanted on day 7 after STZ treatment in order to keep blood glucose around 300 mg/dL. At the end of experiments the animals were sacrificed and the kidneys were flushed and collected for analysis. We did not measure any difference in plasma aldosterone levels between STZ‐treated and control animals. However, single channel patch‐clamp analysis of ENaC activity in isolated split‐opened tubules revealed that high blood glucose levels increased channel activity compared to normoglycemic animals (NPo were 1.57±0.20 and 0.59±0.19 in STZ‐treated and control animals, respectively). Western blotting and immunohistochemical analyses revealed greater abundance of beta‐ENaC subunits in the kidney cortex of hyperglycemic rats. We conclude that high blood glucose levels in T1D cause ENaC hyperactivity that can lead to excessive sodium and water reabsorption.Support or Funding InformationSupported by NIH R00HL116603, R01HL056259.
The SGLT2 Inhibitor, Empagliflozin, Attenuates Some Markers of Renal Fibrosis without Improving Albuminuria in Diabetic Db/Db Mice
Authors: Gallo Linda A , Ward Micheal S , Fotheringham Amelia K , Zhuang Aowen , Koepsell Hermann , Vallon Volker , Pollock Carol , Panchapakesan Usha , Forbes Josephine M 
Published: November 2023

Sodium‐dependent‐glucose‐transporter 2 (SGLT2) inhibitors are a novel therapy for type 2 diabetes. They block glucose reabsorption by the kidney which promotes urinary glucose excretion and lowers blood glucose levels. We aimed to determine whether SGLT2 inhibition is renoprotective in a mouse model of type 2 diabetes and nephropathy. Male db/db and db/m (C57BLKS/J) mice were administered with once‐daily oral treatment of the SGLT2 inhibitor, empagliflozin (10mg/kg/day), or vehicle from 10–20 weeks of age (n=11/group). These were compared with db/db mice which received metformin (250mg/kg/day) or empagliflozin + metformin co‐therapy (dose as per single). At baseline, all db/db mice were obese with hyperglycemia (P<0.05). Towards the study end, these mice had glomerular hyperfiltration, albuminuria, increased levels of urinary kidney injury molecule‐1 (KIM‐1), increased kidney weight, tubulointerstitial total collagen accumulation, glomerulosclerosis, and increased renal expression of pro‐fibrotic genes (P<0.05). Treatment with empagliflozin, either as a mono‐ or co‐therapy, improved glycemic control compared to vehicle (glycated hemoglobin 6.6% and 5.7%, respectively, vs 9.6%, P<0.05) but did not reduce albuminuria, urinary KIM‐1, kidney weight, or glomerulosclerosis. Empagliflozin in diabetic mice reduced total collagen accumulation and renal expression of Fn1 and Tgfb1 and, when co‐administered with metformin, also attenuated the increased renal cortical expression of ColIV and Ctgf, and glomerular hyperfiltration (P<0.05). Empagliflozin, alone or in combination with metformin, increased intra‐renal renin activity compared to vehicle‐treated diabetic mice (P<0.05) but did not increase cortical angiotensin II content. In this mouse model of diabetic nephropathy, blood glucose lowering with SGLT2 inhibition did not improve albuminuria but attenuated some histological and molecular markers of renal fibrosis. Hyperglycemia and albuminuria‐onset prior to commencement of treatment may have been sufficient for disease development and rendered our study an interventional approach. Thus, early, sufficient, and stable blood glucose lowering with SGLT2 inhibition, possibly in combination with RAS blockade, may be required to achieve maximal renoprotection in diabetes. Further, the potential for SGLT2 inhibition to slow progression to more advanced stages of kidney disease remains to be assessed.Support or Funding InformationNational Health and Medical Council of Australia and Heart Foundation (Australia). Boehringer‐Ingelheim (Germany) provided the empagliflozin.