bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antioxidant Therapy Attenuates Post‐Infarct Left Ventricular Remodeling by Driving Expression of the Transcriptional Repressor Krüppel‐Like Factor 15
Authors: Rogers Russell George , Otis Jeffrey Scott 
Published: November 2023

BackgroundCardiovascular disease and heart failure are responsible for approximately 33% of all‐cause mortality in the United States. The causes of heart failure following myocardial infarction (MI) are diverse, but research has implicated oxidative stress as a key pathological driving force.MethodsMI was surgically induced following ligation of the left anterior descending coronary artery. Subgroups of MI rats received resveratrol (i.p., 10 mg/kg/day for 28 days beginning immediately post‐MI). Cardiac histology and Krüppel‐like factor 15 (KLF15) expression were analyzed.ResultsMI resulted in a significant reduction in the expression of KLF15, a transcriptional repressor to pro‐hypertrophic and pro‐fibrotic genes. Further, MI increased cardiomyocyte cross‐sectional area approximately 2‐fold compared to sham operated animals. MI rats that received resveratrol had an increased expression of nuclear factor (erythroid‐derived 2)‐like 2, a master antioxidant transcription factor that may suggest a reduction to oxidative stress. Further, resveratrol increased expression of KLF15 and attenuated infarct scar size and cardiomyocyte hypertrophy.ConclusionsThese results indicate a previously unknown redox‐sensitive mechanism to pathological remodeling following MI and suggest that therapeutic interventions targeting KLF15 signaling may improve cardiac health following MI.Support or Funding InformationGeorgia State University Internal Research Grant
Glucose Promotes Metabolic Reprogramming of Male Rat Hearts in the Early Stress Response Following Hypothermic Ischemic Arrest and Reperfusion
Authors: Bux Ahmed , Vasquez Hernan , Taegtmeyer Heinrich , Harmancey Romain 
Published: November 2023

The mechanisms by which hyperglycemia increases mortality in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are not well defined. The present study aimed to elucidate the effects of glucose on early cardiac remodeling following cardiac arrest and reperfusion. Isolated hearts of male Sprague Dawley rats were cold‐arrested and subjected to 60 minutes normothermic reperfusion in the working mode with Krebs‐Henseleit buffer supplemented with glucose (25 mM) or mannitol (25 mM; osmotic control). Alterations of gene expression in the left ventricle were then determined by microarray analysis. Compared to non‐perfused hearts, perfused hearts displayed a more than twofold increased expression for 71 genes (mannitol group) and 103 genes (glucose group) connected to inflammation, apoptosis, and remodeling. There was a significant overlap between the transcriptional changes found in the perfused rat hearts and gene alterations previously reported in the right atrium (p < 2.34E‐16) and left ventricle (p < 4.83E‐46) of patients who underwent cardiac surgery with CBP. A rank‐rank hypergeometric overlap analysis of the genes differentially expressed in perfused hearts demonstrated that the transcriptional remodeling occurred independently from the presence of glucose. However, compared to hearts perfused with mannitol, glucose further increased the expression of early stress response genes and master regulators of metabolic reprogramming Myc (+ 56%), Nr4a1 (+ 30%), and Nr4a2 (+ 76%). This was accompanied by the increased expression of enzymes and membrane transporters controlling metabolic flux in pathways associated with the activation of immune cells and fibroblasts, including glycolysis (HK2, SLC2A3), glutamine catabolism (SLC1A5, GLS), fatty acid biosynthesis (OLAH), polyamine biosynthesis (ARG1, SAT1), and hexosamine biosynthesis (UAP1, GFPT1). Interestingly, glucose failed to enhance the expression of these transcription factors and enzymes in the heart of rats rendered insulin resistant by high‐sucrose feeding. This study demonstrates that the isolated working rat heart accurately reproduces the stress response associated with cardiac surgery with CPB. The results also suggest that glucose promotes the activation of resident cardiac immune cells and stromal cells in the stressed heart by enhancing their metabolic reprogramming. Lastly, we demonstrate that insulin resistance blocks the metabolic reprogramming induced by glucose in the isolated heart.Support or Funding InformationSupported by grants K99/R00 HL112952 (to R.H.) and R01 HL061483 (to H.T.) from the National Institutes of Health
Na+,HCO3−‐cotransporter NBCn1 promotes Filopodia Generation, Smooth Muscle Cell Migration And Conduit Artery Remodeling
Authors: Aalkjaer Christian , Boedtkjer Ebbe , Bentzon Jacob Fog , Dam Vibeke Secher 
Published: November 2023

We tested the role of cellular acid‐base transport in vascular smooth muscle cell (VSM) proliferation and migration and in structural remodeling of conduit arteries.We used VSM from primary explants of mouse carotid arteries and aorta. In primary explants, pHi gradients exist along the axis of VSMC migration. In the presence of CO2/HCO3−, but not in its absence, knockout or pharmacological inhibition of the Na,HCO3‐cotransporter NBCn1 abolishes the pHi gradients, reduces filopodia generation and lowers the initial rate of VSMC migration after wound infliction. Interventions to reduce buffer mobility (omission of CO2/HCO3− or inhibition of carbonic anhydrase) reestablish pHi gradients and migration velocity in NBCn1 knockout mice. In vivo, carotid arteries undergo hypertrophic inward remodeling in response to ligation but the increase in media area and thickness and the reduction in lumen diameter are attenuated in arteries from NBCn1 knockout compared to wild type mice.With CO2/HCO3− present, NBCn1‐mediated HCO3− uptake promotes filopodia generation and migration. Knockout of NBCn1 inhibits hypertrophic inward remodeling of carotid arteries. We propose that acid‐base transport, particularly via NBCn1, is a promising target for treatment of occlusive artery disease.Support or Funding InformationDanish Research Council, Danish Heart Foundation
High Affinity Bent β2 Integrin Binds Ligand in Cis and Regulates Inflammation
Authors: Fan Zhichao , McArdle Sara , Mikulski Zbigniew , Gutierrez Edgar , Ginsberg Mark , Groisman Alex , Ley Klaus 
Published: November 2023

Integrins are bidirectional signaling molecules that are bent at rest. Upon cell activation, integrins can extend (E+) and acquire a high affinity conformation with an “open” headpiece (H+). The canonical “switchblade” model of integrin activation proposes that the E+ conformation precedes H+, and the two are thought to be structurally linked. Only the E+H+ conformation can mediate cell adhesion by binding to ligand in trans. Here, by using high‐resolution quantitative dynamic footprinting (qDF) microscopy combined with a homogenous conformation‐reporter binding assay, we show that a substantial fraction of β2 integrins on human neutrophils acquires an unexpected E−H+ conformation not previously seen on primary cells. We show that E−H+ integrin is functional because it binds its ligand intercellular adhesion molecule 1 (ICAM‐1) in cis and significantly inhibits neutrophil adhesion under flow, which is demonstrated by Förster resonance energy transfer assay, qDF imaging and microfluidic neutrophil adhesion assay and intravital cremaster imaging on neutrophil adaptive transfered mice. These findings suggest that integrin extension does not necessarily precede high affinity and the two are regulated independently.Support or Funding InformationNIH funding HL078784
Endothelial Cell Secreted MIF Regulates Pericyte Contractility to Decrease Barrier Function
Authors: Pellowe Amanda , Hou Yue , Harris Mariah , Liu Rebecca , Pober Jordan S , Gonzalez Anjelica 
Published: November 2023

Microvascular endothelial cells (EC) and pericytes (PC) regulate neutrophil (PMN) transmigration through a variety of mechanisms, including adhesion molecule expression and contractility. Specifically, the contraction of endothelial cells creates F‐actin docking structures rich in intercellular adhesion molecule 1 (ICAM‐1) expression and generates gaps between cells that allow for PMN transmigration. Recent evidence has alternatively suggested that PC relaxation, rather than contractility, results in the loss of focal adhesions, disassembly of stress fibers, and subsequent increase in PMN transmigration. Both in vivo and in vitro experimental systems of composite EC/PC microvascular constructs demonstrate that PC are less permissive to neutrophil transmigration in the absence of EC, suggesting that communication between EC and PC may regulate PC contractility. Here, we demonstrate that tumor necrosis factor alpha (TNFa) induced EC secretion of the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF), which is accompanied by a TNFa induced upregulation of the MIF receptor (CD74) in PC, significantly decreases PC contractility. We confirm that TNFa mediated transmigration is differentially regulated by contractility. EC contractile ability is required to facilitate PMN transmigration through the formation of F‐actin docking sites and ICAM‐1 localization. In contrast, inhibition of PC contractility increases PMN transmigration via mechanisms that are not related to the loss of ICAM‐1 localization and F‐actin disassembly, but rather the loss of focal adhesion plaques, the loss of tension fibers and the formation of PC junctional gaps. We have confirmed that EC secreted MIF signaling results in the loss of PC focal adhesion plaques and significantly decreases PC contractility. This study suggests for the first time that EC paracrine signaling can mediate PC regulated PMN transmigration, and specifically that EC to PC MIF signaling may be an important factor for reducing PC barrier function during inflammation.Support or Funding InformationDubinsky Initiative
A BIOPOLYMER‐STABILIZED VEGF CHIMERA REVERSES ANGIOGENIC IMBALANCE IN THE REDUCED UTERINE PERFUSION PRESSURE MODEL OF PREECLAMPSIA
Authors: LOGUE OMAR CHRISTOPHER , Mahdi Fakrhi , George Eric Matthew , Bidwell Gene Lee 
Published: November 2023

Preeclampsia (PE) is a hypertensive disorder that complicates approximately 5–8% of all pregnancies. The unknown etiology of PE originates from defective spiral artery remodeling at the maternal‐placental interface. The resulting hypoxia creates placental ischemia from which the anti‐angiogenic factor soluble fms‐like tyrosine kinase‐1 (sFlt‐1) is released. sFlt‐1 sequesters VEGF from binding to fully functional VEGF receptors, leading to endothelial dysfunction and maternal hypertension. The rodent model of PE, reduced uterine perfusion pressure (RUPP), exhibits the sFlt‐1 pathophysiology observed in human PE. To restore endothelial function impaired by excessive placental sFlt‐1 production, we have constructed a VEGF chimera fused to an Elastin‐like Polypeptide (ELP) carrier with increased in vivo half‐life and stability. We observe that ELP‐VEGF exhibits potency equal to that of free VEGF in stimulating tube formation in human umbilical vein vascular endothelial cells (HUVEC) cells exposed to serum from pregnant RUPP Sprague‐Dawley rats. Moreover, intraperitoneal administration of ELP‐VEGF at 5 mg/kg/day ameliorates hypertension in timed pregnant RUPP rats. Pharmacokinetic and biodistribution studies of this therapeutic dose demonstrate nearly complete fetal exclusion. These data indicate that ELP‐delivered VEGF has the potential to preserve endothelial function by counteracting the anti‐angiogenic factors circulating in the maternal plasma while preventing fetal exposure to VEGF supplementation.Support or Funding InformationAHA 13SDG16490006 to BidwellNHLBI 1R01HL121527 to BidwellNHLBI 1R00HL116774 to GeorgeRuth L. Kirschstein INRSA 5 T32 HL 105324‐5 to Logue
Decreased Uterine Vascularization and Uterine Arteriolar Expansive Remodeling by Matrix Metalloproteinases in Hypertensive Pregnancy
Authors: He Hong , Lin Chen , Ren Zongli , Zhu Minglin , Khalil Raouf A 
Published: November 2023

Normal pregnancy is associated with extensive remodeling of spiral arteries in order to maintain nutrients and blood supply to the growing fetus. Inadequate placentation and invasion of the uterine wall could lead to uteroplacental ischemia and hypertensive pregnancy (HTN‐Preg); however, the extent of uterine vascularization and the mechanisms involved are unclear. We hypothesized that HTN‐Preg is associated with changes in uterine vascularization and arterial remodeling by matrix metalloproteinases (MMPs). Blood pressure (BP) and fetal parameters were assessed on day‐19 in normal pregnant rats (Preg) and pregnant rats with reduced uterine perfusion pressure (RUPP), and the uteri were isolated for measurement of tissue vascularity and MMPs expression/activity. BP was greater and pups number and weight, and uterus weight were reduced in RUPP vs. Preg rats (BP 128.2±1.7 vs. 91.60±2.8mmHg; pups number 8.8±1.1 vs. 13.00±0.7; pup weight 1.48±0.059 vs. 2.02±0.02g; uterus weight 3.82±0.37 vs. 4.92±0.27g). Histological analysis of uterine tissue sections showed reduced total number and whole area of uterine arterioles in RUPP vs. Preg rats (number 5.75±0.95 vs. 11.50±0.87; area 0.05±0.01 vs. 0.12±0.02mm2). Immunohistochemistry with the endothelial cell marker CD31 showed localization in the uterine arterial intima and confirmed reduction in the number and size of uterine arterioles in RUPP vs. Preg rats. Further analysis of the uterine arterial wall showed reduction in the area of all three layers of the uterine arterial wall in RUPP vs. Preg rats (intima 0.015±0.003 vs. 0.031±0.005; media 0.012±0.002 vs. 0.038±0.005; adventitia 0.021±0.003 vs. 0.048±0.007mm2). Western blots and gelatin zymography showed a decrease in expression and activity of MMP‐2 and ‐9 in uterus and uterine arteries of RUPP vs. Preg rats. Immunohistochemistry showed decreased total amount of MMP‐2 and ‐9 in the uterus, and reduction in MMP distribution in the intima and media of uterine arteries of RUPP vs. Preg rats. Thus, in HTN‐Preg rats there is reduction in the number and size of uterine arteries and decreased expression and activity of MMP‐2 and ‐9. These results suggest that reduced uterine vascularization and uterine arteriolar expansive remodeling by MMPs could be a factor in the uteroplacental ischemia associated with HTN‐Preg and preeclampsia.Support or Funding InformationThis work was supported by grants from National Heart, Lung, and Blood Institute (HL‐65998,HL‐111775).
Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult Offspring
Authors: Bourque Stephane L , Care Alison , Sung Miranda , Panahi Sareh , Gragasin Ferrante , Davidge Sandra T , Dyck Jason R 
Published: November 2023

BackgroundThe spontaneously hypertensive rat (SHR) is a model of essential hypertension in which high blood pressure (BP) develops after 7 wks of age. Altered vascular resistance profiles and renal hemodynamics are evident by 3 wks of age, implicating these early functional changes as a cause, rather than a consequence, of hypertension in this model. As such, the developmental period before weaning may constitute a critical time for therapeutic intervention.ObjectiveThis study was undertaken to determine whether perinatal maternal resveratrol (Resv)—a phytoalexin known to confer cardiovascular protection—could prevent the development of hypertension and improve vascular function in adult SHR offspring.MethodsSHR dams were fed either a control or a Resv‐supplemented diet (4g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess BP and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo.ResultsPerinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by PD21; growth restriction was no longer evident after 5 wk of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (−18mHg, P=0.007), and L‐NAME treatment normalized these BP differences, suggesting improved NO bioavailability underlies the BP reductions in the SHR+Resv group. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L‐NAME attenuated the vasodilation in SHR, but not SHR+Resv adult offspring, suggesting a shift towards NO‐independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor bET‐1 to active ET‐1 in isolated mesenteric arteries was reduced in SHR+Resv offspring (−28%; P<0.05), and this difference could be normalized by L‐NAME treatment.ConclusionPerinatal Resv mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in SHRs.Support or Funding InformationThis work is funded by grants from the Canadian Institutes of Health Research and the Women and Children's Health Research Institute through the generous contributions of the Stollery Children's Hospital Foundation and the Royal Alexandra Hospital Foundation. AC was supported by fellowships from the National Health and Medical Research Council of Australia, Alberta Innovates ‐ Health Solutions, and the Heart and Stroke Foundation of Canada; SD is a Canada Research Chair in Maternal and Perinatal Cardiovascular Health.
Cardiometabolic Risk Factors in the Mouse are Shaped by Metabolic State of the Mother During Pregnancy
Authors: Thompson Jennifer Anne , Mintz James 
Published: November 2023

ObjectiveTo determine if gestational diabetes (GDM) programs an aberrant cardiometabolic phenotype in the offspring.MethodsAt 14 weeks of age and after assessment of pre‐conception metabolic status, female wild type (Wt) and female mice heterozygous for the leptin receptor mutation (Hetdb) were mated with Wt males. To confirm development of GDM, intra‐peritoneal glucose tolerance tests (IPGTT) were performed on Gd17 (term = Gd19) in Wt and Hetdb pregnant females. Maternal body composition was determined by NMR spectroscopy. One group of pregnant females was sacrificed on Gd18 for collection of maternal blood; the second group delivered spontaneously. Only Wt offspring were examined. At 3‐weeks (weaning), 3‐months and 6‐months of age, offspring were evaluated for body composition using NMR. At 6‐months, fasting plasma levels of lipids were determined by Colorimetric assay.ResultsPrior to conception, regulation of blood glucose appears normal in Hetdb females compared to Wt controls, yet non‐pregnant Hetdb females displayed increased adiposity and reductions in lean body mass relative to age‐matched, non‐pregnant controls (p < 0.001). On Gd17 there was an increase in fasting blood glucose, insulin and triglyceride levels, and reduction in glucose clearance in pregnant Hetdb vs. Wt females (all p < 0.05). At 3‐weeks of age, % body fat was increased in male (p < 0.001) and female (p < 0.001) Wt offspring born from a Hetdb dam (Male: Wt dam 6.6 ± 0.4 %, Hetdb dam 10.8 ± 0.8 %; Female: Wt dam 7.0 ± 0.37 %, Hetdb dam 10.4 ± 0.7 %). At 3‐months and 6‐months, adiposity remained higher in offspring born to Hetdb dams (p < 0.05). At 6‐months, fasting plasma triglyceride levels were increased 2‐fold in Wt offspring of Hetdb vs. Wt pregnancies; non‐esterified fatty acids (p < 0.01) and cholesterol (p < 0.05) levels were increased by 54% and 68%, respectively, in Wt offspring of Hetdb pregnancy.ConclusionsThe Hetdb female has high pre‐pregnancy adiposity and spontaneously develops glucose intolerance during pregnancy and thus is a valuable model for the study of GDM. Similar to human GDM, the Hetdb model programs an abnormal metabolic phenotype in the offspring.Support or Funding InformationJAT supported by AHA 15POST25730006JAT
Increased hepatic lipogenic gene expression correlates with enhanced central and ectopic adiposity in female C57BL/6 mice exposed to maternal separation
Authors: Murphy Margaret , Cohn Dianne , Wills Caleb , Gilbert Lucas , Powell David , Loria Analia 
Published: November 2023

We previously reported that maternal separation (MatSep), a model of early life stress, in combination with high fat (HF) diet leads to exaggerated weight gain; however, female mice present with significantly greater levels of adiposity compared to male mice. The objective of this study was to investigate the sex‐specific differences within MatSep mice in driving fat tissue expansion by measuring 1) food intake and energy expenditure (EE), 2) body fat distribution using MRI, 3) ectopic lipid deposition, 4) systemic and local production of CORT, and 5) liver and white adipose tissue (WAT) gene expression in response to HF diet. MatSep was performed in male and female C57Bl/6 mice with early weaning at PND17 and mice were weaned onto a HF diet for 16 weeks. Normally reared mice served as controls (C). A group of mice (n=6–10) were placed into TSE metabolic chambers to obtain net food intake and EE normalized to lean body mass. In female mice, food intake was significantly higher in MatSep compared to C mice (slope: 0.522±0.59 vs −2.67±1.79, p<0.05) with no differences observed between groups in male mice. MatSep had no effect on EE in both male and female mice. MRI analysis revealed elevated levels of visceral fat in MatSep female mice compared to C (1550.7 ± 233.5 vs 904.1 ± 104.5 mm3 p=0.08, n=4). In addition, oil Red O staining within the liver and kidney revealed an elevated accumulation of neutral lipids suggesting that MatSep increases both central and ectopic adiposity. In response to HF diet, plasma levels of CORT were not different between MatSep and C in male (145.8 ± 38.6 vs. 111.04 ± 35 ng/ml, respectively) and female mice (193.8 ±36.3 vs. 176.5 ± 31 ng/ml, respectively, 2‐way ANOVA: NS, n=6). RT‐PCR analysis revealed that MatSep upregulated 11β‐HSD1 in subcutaneous WAT in both genders; however, only female MatSep mice showed upregulation of 11β‐HSD1 in liver (3.71±0.61 vs 0.82±0.37 2^ddCt, p<0.05, n=6–8) suggesting an elevated local CORT regeneration. In addition, we found a significant upregulation of several hepatic lipogenic genes including PPARγ, ACC‐1, FAS, SCD‐1, and CREB in MatSep females compared to C. No differences between MatSep and C were found in hepatic lipogenic genes from male mice. Interestingly, obese MatSep female mice showed increased ER β expression compared to C in gonadal WAT (113.91±22.63 vs. 1.41±0.43 2^ddCt, p<0.05) and SQ WAT (56.34±11.19 vs 1.05±0.23 2^ddCt, p<0.05) which may have diabetogenic effects. No differences in ER β expression were observed in male mice. We propose that excessive glucocorticoid signaling at the tissue level may contribute to the exacerbated lipogenesis and fat expansion in female mice exposed to MatSep, suggesting a potential mechanism by which female mice exposed to early life stress develop metabolic dysfunction.Support or Funding InformationNIH R00 HL111354 COBRE P20 GM103527‐06