bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pro‐atherogenic disturbed flow increases endothelial stiffness via enhanced CD36/Cav1‐ mediated oxLDL uptake
Authors: LeMaster Elizabeth , Shentu Tzu‐Pin , Huang Ru‐Ting , Zhang Chongxu , Adamos Crystal , Fancher Ibra , Ng Carlos , Christoforidis Theodore , Subbaiah Papasani , Eddington David , Cho Michael , Fang Yun , Minshall Richard , Levitan Irena 
Published: November 2023

ObjectiveDisturbed flow (DF) is known to induce endothelial dysfunction and synergistically with plasma dyslipidemia promote plaque formation. Little is known, however, about the synergistic impact of DF and dyslipidemia on endothelial biomechanical properties. Our goal was to determine the impact of DF on endothelial stiffness and evaluate the role of dyslipidemia/oxidized low density lipoprotein (oxLDL) in this process.Methods and ResultsEndothelial elastic modulus of intact mouse aortas ex vivo and of human aortic ECs (HAECs) exposed to laminar or disturbed flow in vitro was measured using atomic force microscopy. The endothelial monolayer of the aortic arch (AA) was found to be significantly stiffer than the descending aorta (DA) (4.2+1.1 vs. 2.5+0.2 kPa for AA vs. DA) in mice maintained on low fat diet (LFD). This effect was significantly exacerbated by a short‐term high‐fat diet (HFD) (8.7+2.5 vs. 4.5+1.2 kPa for AA vs. DA). Exposure of HAECs to DF in vitro resulted in a 50% increase in oxLDL uptake and significant endothelial stiffening in the presence but not in the absence of oxLDL. DF was shown to increase the expression of oxLDL receptor CD36 and the downregulation of CD36 abrogated DF‐induced endothelial oxLDL uptake and stiffening. ECs deficient in caveolin1 (Cav1) had no significant oxLDL uptake and no DF‐induced EC stiffening. Furthermore, genetic deficiencies of CD36 and of Cav1 abrogated endothelial stiffening in the aortic arch ex vivo in mice fed either LFD or HFD.ConclusionsDisturbed flow facilitates endothelial CD36/Cav1‐dependent uptake of oxidized lipids resulting in a local increase of endothelial stiffness in pro‐atherogenic areas of the aorta.Support or Funding InformationThis study is supported by NIH grants HL‐073965 (IL,DE), HL‐083298 (IL,RM,MC,PVS), and R00 HL‐103789 (YF); AHA MWA Pre‐doctoral Fellow 14PRE20490156 (EL) and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust (DE).
ENDOTHELIAL FUNCTION AND ANTIOXIDANT CAPACITY ARE IMPAIRED IN ADULTS WHO REPORT ADVERSE CHILDHOOD EVENTS
Authors: Miguelez Paula Rodriguez , Looney Jacob , Blackburn Marsha , Thomas Jeffrey , Pollock Jennifer , Harris Ryan 
Published: November 2023

INTRODUCTIONAdverse childhood events (ACEs), comprised of adversity early in life among others, have been associated with the development of cardiovascular disease (CVDs) during adulthood. Endothelial dysfunction plays a pivotal role in the etiology of CVDs and has been associated with higher production of reactive oxygen species (ROS). Apart from the body's endogenous ability to counteract ROS, the consumption of exogenous antioxidants also enhance the capacity to scavenge free radicals and improve endothelial function. Whether or not ACEs predisposes adults to a reduction in antioxidant capacity and an impaired endothelial function has yet to be investigated.PURPOSEThis study sought to test the hypotheses that 1) ACEs contribute to a lower total antioxidant capacity and an impaired endothelial function, and 2) the ingestion of oral antioxidants will increase antioxidant capacity and improve endothelial function.METHODSForty‐four young adults (34 ± 3 yrs), with no evidence of overt CVDs, were divided into two groups based on their self‐reported ACE questionnaire score: HiA: ACE score ≥ 4 (n=15) or NoA: ACE score = 0 (n=29). Utilizing a randomized, placebo‐controlled, crossover experimental design, flow‐mediated dilation (FMD), an index of endothelial function, and plasma total antioxidant capacity (TAC) were assessed in all participants at baseline and following ingestion of either placebo (P) or an antioxidant cocktail (AOC: vitamin C, vitamin E and α‐lipoic acid) on separate days.RESULTSAt baseline, TAC tended to be lower in HiA compared with NoA (2.01 ± 0.42 vs. 2.47 ± 0.93 mM; p=0.063, respectively). FMD was significantly (p=0.026) lower in HiA (6.5 ± 3.0 %) compared to NoA (8.5 ± 2.8 %). In addition, a significant moderate correlation between TAC and FMD (r=0.350; p=0.022) was identified at baseline. After the AOC, a significant increase (p=0.049) in TAC was only observed in NoA compared with HiA (ΔTAC: 0.29 ± 0.01 vs. 0.09 ± 0.02 mM, respectively). Likewise, FMD was significantly (p=0.037) higher after the AOC in NoA (ΔFMD: 1.5 ± 0.2 %) and unchanged in HiA (ΔFMD: 0.1 ± 0.1 %). No differences in either TAC or FMD (p≥0.321) were observed after the P in either group.CONCLUSIONFor the first time, we have documented that adults who reported ACEs exhibit a lower antioxidant capacity and impaired endothelial function compared with adults who did not report ACEs. However, an acute AOC was only able to improve antioxidant capacity and endothelial function in those individuals who did not experience ACEs. Future studies are warranted to evaluate possible therapies to improve antioxidant capacity and vascular function in adults who experienced ACEs.Support or Funding InformationSupport in part by NIH/NHLBI P01HL06999 (RAH).
Voluntary Exercise Enhances Cardiac Growth in Response to Chronic β‐Adrenergic Receptor Stimulation
Authors: Lenth Moira Kate O'Connor , Soo Sherilynn , Luckey Stephen , McLaughlin Nathan 
Published: November 2023

Exercise has been demonstrated to protect the heart against the adverse effects of cardiovascular disease. Given the prevalence of cardiovascular disease (CVD), the role that exercise plays in protecting the heart prior to CVD is an important area of research given its clinical implications. Therefore, this study aims to examine how voluntary exercise can impact the progression of heart failure. To do this, a mouse model with nine‐week‐old female and male CB6F1 hybrid mice was used to test the impact of voluntary wheel running on heart failure resulting from chronic β‐adrenergic receptor stimulation. Mice either exercised for five weeks on a voluntary wheel (EX) or remained sedentary during the duration of the study (SED). After three weeks, both SED and EX mice were administered either vehicle (VEH) or isoproterenol (ISO, 30mg/kg/day) via an osmotic pump for two weeks. In the EX group, mice were further divided into two groups: one that continued exercising while receiving ISO (EX+ISOe) and one that became sedentary (EX+ISOs). At the end of the treatment, morphometric data was collected including heart weight‐to‐tibia length (HW/TL). Significant cardiac growth was observed in the both males and females in the mice that exercised for the entire five weeks (EX+VEH) as compared to their sedentary counterparts (SED+VEH). Additionally, male and female mice that were sedentary for 21 days and received ISO (SED+ISO) had increased heart size in comparison to the control group (SED+VEH). In male and female EX+ISOs mice, both sexes had similar cardiac growth to the SED+ISO group. Finally, cardiac growth in both EX+ISOe males and female was greater than any of the other groups of mice. Our results suggest that there is an additive effect of both exercise and ISO causing this significant increase in size. This data is in contrast to previous studies that demonstrated forced exercise reduced cardiac hypertrophy in response to chronic β‐adrenergic receptor stimulation. To better understand these differences in our study, we are currently performing quantitative PCR on left ventricular tissue to identify changes in a number of hypertrophic gene markers. These investigations will allow us to better understand the cardioprotective effects of exercise on the progression of heart failure.Support or Funding InformationMurdock Faculty Start‐up Funding (SL)
Multiple Sclerosis Patients Do not Show Changes in Wave Intensity Analysis Following Home‐Based Exercise
Authors: Griffith Garett , Wee Sang Ouk , Klaren Rachel , Motl Robert , Baynard Tracy , Fernhall Bo 
Published: November 2023

Physical inactivity and a host of other behavioral and lifestyle characteristics result in increased prevalence rates of cardiovascular disease (CVD) among multiple sclerosis (MS) patients. Non‐invasive assessment techniques can quantify arterial dysfunction, and have been shown to detect positive arterial responses to aerobic exercise training. Wave intensity analysis (WI), an ultrasound measurement which serves as a surrogate measure of ventricular‐arterial interaction, is one such non‐invasive methodology. Our purpose was to determine if WI changes as a result of home‐based aerobic exercise in MS patients. Participants completed either a 3 month home‐based aerobic exercise (N=26, 49±11 years) or stretching (N=22, 43±13 years) intervention. Exercisers completed 3 days per week of moderate intensity cycling (progressing from 40% to 60% of aerobic capacity and from 10 to 30 minutes), and stretchers completed 3 days per week of a whole body routine (progressing from 5 to 20 stretches). Ultrasound assessments of the carotid artery were performed after 15 minutes of supine rest at baseline and after 12 weeks. Carotid blood pressures were measured with applanation tonometry and entered into the ultrasound. P < 0.05 for all analyses. Group differences at baseline were found for carotid artery diameter difference, WD1, and velocity range. No Time*Group interactions were found for any WI variables. See table 1 for carotid artery WI analysis results. Our data suggest that 3 months of home‐based aerobic exercise at moderate intensity is insufficient to impact wave intensity in multiple sclerosis patients. Since WI is able to assess ventricular‐arterial interaction at a specific point in the arterial tree, future studies in this population should consider assessing WI in locations different than the carotid artery. Additionally, effects on WI of increased volume of aerobic exercise have yet to be explored in this population.Support or Funding InformationThis project was supported by the National Multiple Sclerosis Society RG 4702A1/2.
Data are presented as Mean ± SD.

Baseline
12 Weeks

Stretching (N=22)
Exercise (N=26)
Stretching (N=22)
Exercise (N=26)

Diameter Δ (cm)#
0.50 ± 0.11
0.41 ± 0.14
0.49 ± 0.13
0.43 ± 0.15

1st (w1)
9152.3 ± 5901.4
7431.3 ± 4925.5
10500.0 ± 8296.1
6975.8 ± 6361.3

Wd1 (m/s3)#
19.7 ± 16.1
12.5 ± 9.7
18.7 ± 13.6
11.7 ± 11.6

2nd (w2)
552.3 ± 648.9
1275.0 ± 1246.2
940.9 ± 970.6
1162.5 ± 1203.0

Wd2 (m/s3)
1.0 ± 1.3
1.9 ± 2.0
1.5 ± 1.5
1.8 ± 1.9

Velocity Range (cm/s)#
44.5 ± 16.9
35.3 ± 13.7
48.7 ± 14.5
41.0 ± 14.5

* Interaction (Time*Group).
Difference between Stretching and Exercise at baseline.
Relationships between Functional Capacity and Hemodynamic Characteristics in Patients with Peripheral Arterial Disease
Authors: Fu Tieh‐Cheng , Lin Yu‐Ching , Soh‐Ching NG , Wang Jong‐Shyan , Yeh Chi‐Hsiao 
Published: November 2023

Peripheral arterial disease (PAD) causes chronic narrowing of arteries and reduces the capacity of blood flow to the legs, which can progress in severity to greatly limit mobility in the patients. What kind of exercise test serves as a functional indicator of PAD progression needs for further investigation. Sixty‐four patients with PAD were recruited and subsequently performed three exercise tests [6 minutes walking test (6MWT), 3 minutes stepping test (3MST) and cardiopulmonary exercise test on a bicycle ergometer (CPET)]. Magnetic resonance angiography (MRA) was adopted to measure hemodynamic characteristics, whereas sphygmomanometry and duplex ultrasonography were employed to assess arterial brachial index (ABI). The results demonstrated that the values of ABI were associated with the levels of blood flow in posterior tibial artery/peroneal artery/femoral artery, but not relative to the measures of CPET, 6MWT or 3MST. However, the initial pain time in CPET or 3MST was associated with the initial pain distance of 6MWT. Additionally, functional parameters of CPET and 6MWT were positively correlated with hemodynamic parameters of MRA. Therefore, we conclude that functional parameters obtained from 6MWT and CPET effectively predict hemodynamic characteristics in patients with PAD.Support or Funding InformationChang Gung Memorial Hospital, Keelung, Taiwan (CMRPG2F0191)Ministry of Science and Technology, Taiwan (105‐2314‐B‐182A‐130‐)
Parkin‐Mediated Mitophagy in Skeletal Muscle with Endurance Training
Authors: Chen Chris , Hood David 
Published: November 2023

Skeletal muscle is a highly adaptive tissue that is responsive to environmental cues. With exercise training, intracellular signaling pathways are activated that promote the synthesis of mitochondria, a process termed biogenesis. The increased number of mitochondria allows for efficient substrate utilization and greater muscle endurance. However, little is known regarding mitochondrial turnover with training. Mitophagy is a process involved in the specific elimination of dysfunctional mitochondria. It is unclear if mitophagy undergoes adaptive responses in muscle with training. Parkin is a ubiquitin ligase involved in neuronal mitophagy but its role in muscle remains inconclusive. To investigate Parkin's role in muscle with exercise training, we subjected 3‐month‐old wild‐type (WT) and Parkin knock out (KO) mice to a 6‐week voluntary wheel running training paradigm. Overall, WT mice ran 28% longer than KO mice in average total running distance. Endurance training elicited 1.5‐ and 1.4‐fold increases in whole muscle mitochondrial content in WT and KO mice, respectively. Furthermore, subunits I and IV of cytochrome c oxidase and mitochondrial transcription factor A were augmented on intermyofibrillar mitochondria (IMF) isolated from hindlimb muscles of trained WT animals. This was supported by a 1.7‐fold increase in State 3 (active) IMF respiration in trained WT mice. Following 6 weeks of training, both Parkin KO and WT mice exhibited 2‐fold increases in running performance during an exhaustive bout of exercise, compared to their untrained counterparts. Interestingly, basal mitophagy flux and mitochondrial localization of LC3II were augmented by 1.5‐fold in muscle of trained WT mice. However, this increase was abolished in KO animals. Acute exercise‐induced a 2‐fold increase in LC3‐II flux in untrained WT mice, which was attenuated to a 1.6‐fold increase with training. In contrast, acute exercise decreased mitophagy flux in untrained and trained KO muscle by 10–20%. Our findings indicate that the localization of autophagy proteins to mitochondria is increased in trained muscle, but is reduced when Parkin is absent. However, during exercise‐induced mitophagy, an attenuation of autophagy proteins localized on mitochondria occurs, which is partly Parkin‐mediated. With training, exercise‐induced mitophagic signaling is reduced, likely due to enhanced mitochondrial biogenesis, leading to improved endurance.Support or Funding InformationSupported by NSERC.
Effect of Exercise Training on Mobilization and Functionality of Endothelial Progenitor Cells undergoing Hypoxic Stress
Authors: Wang Jong‐Shyan 
Published: November 2023

Exercise training improves endothelium‐dependent vasodilation, whereas hypoxic stress causes vascular endothelial dysfunction. This study investigates how high‐intensity interval (HIT) and moderate intensity‐continuous (MCT) exercise training affect mobilization and functionality of endothelial progenitor cells undergoing hypoxic stress. Forty healthy sedentary males were randomized to engage either HIT (3‐minute intervals at 40% and 80%VO2max, n=20) or MCT (sustained 60%VO2max, n=20) for 30 minutes/day, 5 days/week for 6 weeks. Characteristics and functionality of circulating progenitor cells (CPCs) under hypoxic exercise (HE, 100W under12%O2) were determined before and after various interventions. The results demonstrated that both HIT and MCT regimens significantly increased endothelial progenitor cell (EPC) cell count, whereas only HIT considerably increased hemangioblast stem cell (HSC) and endothelial precursor cell (CEP) cell counts at rest and following HE. Moreover, HIT, rather than MCT, significantly diminished the extent of endothelial shedding caused by HE. The HIT regimen also increased resting and HE‐related tube cover area, tube length, and tube count of CPCs. However, MCT did not change migration of CPCs and modestly increased resting tube formation of CPCs at rest or following HE. Therefore, we conclude that HIT is superior to MCT for enhancing functionality of CPCs and suppressing endothelial injury undergoing hypoxia.Support or Funding InformationNational Science Council of Taiwan (grant number NSC 100‐2314‐B‐182‐004‐MY3), Chang Gung Medical Research Program (grant number CMRPD1A0132 and CMRPD2C0161), and Healthy Aging Research Center, Chang Gung University (grant number EMRPD1A0841)
Acute Folic Acid Ingestion Improves Skeletal Muscle Blood Flow during Graded Handgrip and Plantar Flexion Exercise in Aged Humans
Authors: Romero Steven A. , Gagnon Daniel , Adams Amy N. , Cramer Matthew N. , Jaffery Manall F , Kouda Ken , Moralez Gilbert , Crandall Craig G. 
Published: November 2023

Skeletal muscle blood flow is attenuated in aged humans performing aerobic exercise, which is thought to be due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole‐body heating through nitric oxide‐dependent mechanisms. However, it is unclear if folic acid can improve vasodilation in other vascular beds during conditions of increased metabolism (i.e. exercise). Therefore, the purpose of this study was to test the hypothesis that acute folic acid ingestion would improve skeletal muscle blood flow in aged adults during graded handgrip and plantar flexion exercise via increased vascular conductance. Eight healthy aged adults (2 males; age 68 ± 5 years; height 165 ± 6 cm; weight 70 ± 8 kg; mean ± SD) performed graded handgrip (3, 6, 9 kg) and plantar flexion (5, 9, and 14 kg) exercise before (control) and two hours after folic acid ingestion (5 mg). Exercise was performed using a duty cycle of 1 s contraction and 2 s relaxation (20 contractions min−1). Steady‐state forearm (brachial artery) and leg (superficial femoral artery) blood flow and diameter were measured via Duplex ultrasonography. Vascular conductance was calculated as flow/pressure and multiplied by 100. Blood flow and vascular conductance are presented as the mean response across exercise intensity. Acute folic acid ingestion increased serum folate (control 12.8 ± 1.7 ng ml−1 vs folic acid 493.3 ± 85.5 ng ml−1; P < 0.01). During handgrip exercise, folic acid ingestion increased forearm blood flow (control Δ 91 ± 7 ml min−1 vs folic acid Δ 113 ± 9 ml min−1; P < 0.01) and vascular conductance (control Δ 97 ± 7 ml min−1 100 mmHg−1 vs folic acid Δ 114 ± 8 ml min−1 100 mmHg−1; P < 0.01). Similarly, during plantar flexion exercise, folic acid ingestion increased leg blood flow (control Δ 226 ± 19 ml min−1 vs folic acid Δ 284 ± 21 ml min−1; P < 0.01) and vascular conductance (control Δ 244 ± 20 ml min−1 100 mmHg−1 vs folic acid Δ 281 ± 20 ml min−1 100 mmHg−1; P = 0.01). Taken together, acute folic acid ingestion improves blood flow to active skeletal muscle via improved local vasodilation in aged adults.Support or Funding InformationFunded by National Institutes of Health (GM 068865 & GM 117693).
Measurement of Skeletal Muscle Blood Flow with Near‐infrared Diffuse Correlation Spectroscopy
Authors: Rosenberry Ryan , Ganesh Chandan , Tian Fenghua , Nelson Michael D. 
Published: November 2023

Direct continuous noninvasive measurement of local muscle blood flow in humans remains limited. Conventional measurements of limb blood flow, such as Doppler ultrasound or venous occlusion plethysmography, measure changes in bulk conduit flow and do not provide regional information. Near‐infrared diffuse correlation spectroscopy (DCS) is an emerging technique for non‐invasive measurement of local muscle blood flow at the microvascular level. In order to better understand the strengths and limitations of this novel approach, we performed a validation study by comparing muscle blood flow changes measured by DCS and Doppler ultrasound during exercise. Ten subjects were recruited for this study (age: 27±3 yrs; female/male: 1/9; BMI: 27.0±3.6 kg/m2). The DCS probe was affixed to the forearm over the belly of the flexor digitorum profundus. Brachial artery blood velocity and diameter were measured with Doppler ultrasound, integrated, and reported as brachial artery blood flow. After a brief period of rest, each participant performed rhythmic handgrip exercise at 20% and 50% of their maximum voluntary contraction (MVC). As expected, brachial artery blood flow increased significantly from baseline by 312±56% at 20% MVC, and 613±90% at 50% MVC. Blood flow index (BFI), the primary output from DCS, shared a similar change from baseline, increasing 112±18% and 262±35%, respectively. To more appropriately compare these two approaches, the data were normalized to each person's individual maximum for each respective technique. Remarkably, the increase in skeletal muscle blood flow was strikingly similar between the two techniques, when reported in normalized units (20%: 0.42±0.03 vs. 0.45±0.03; 50%: 0.69±0.04 vs. 0.79±0.02, DCS vs. BA flow, respectively). The change in skeletal muscle blood flow by DCS and Doppler ultrasound were also strongly correlated (r2=0.77, P<0.001). Taken together, these data show that DCS and Doppler ultrasound quantify the same temporal dynamics of skeletal muscle blood flow during exercise. While these results are indeed encouraging, more work is needed to fully validate this approach for measuring local microvascular blood flow in humans.Support or Funding InformationThis work was support by an Interdisciplinary Research Program grant from the University of Texas at Arlington.