bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin‐10 (IL‐10) Enhances Wound Healing of Cutaneous Flaps Following Ischemia Reperfusion Injury (IRI)
Authors: Tang Ya Hui , Lian Timothy 
Published: November 2023

Cutaneous flaps are routinely used by reconstructive surgeons for the functional and cosmetic repair of wounds and defects that are the result of burn injuries, trauma, or tumor ablation. Successful reconstructions rely on the survival of these transferred tissues subjected to IRI. We found that IL‐10 is highly and persistently expressed in bone marrow stromal cells (BMSCs) and demonstrated that the introduction of BMSCs into IRI cutaneous flaps has a protective effect.ObjectiveTo determine whether IL‐10 treatment alone can protect cutaneous flaps from IRI or IL‐10 mediates the protective effect of BMSCs therapy in an animal model of cutaneous flaps following IRI.MethodsA 1 × 2 cm cutaneous flap perfused by the inferior epigastric vessels were raised on C57BL/6 wild type and IL‐10−/− mice and were subjected to 3.5 hours of ischemia and then reperfused. Animals were divided into Sham, Ischemia, Ischemia + IL‐10 and Ischemia + BMSCs. IL‐10 and BMSCs were administered intravenously. Both blood perfusion images and perfusion units were recorded by a Laser Speckle Contrast Analysis System at day 1, 3, 5, 7, 9, 14 post ischemia and reperfusion. Digital photography of the flap was performed on the daily basis for analysis of flap size and area of necrosis. Surface area measurements of necrosis was determined with digital image software analysis (Image J; NIH). Biomarkers of endothelial cells (CD31) and immune cells (CD3 and F4/80) were also analysed in IRI flaps using Immunohistochemistry.ResultsThe percent necrosis decreased significantly in mice with either IL‐10 or BMSCs treatment comparison with control on day 3, 5 and 7 post IRI. There was a significant increase in perfusion in all proximal areas at day 5 and distal areas at day 9 compared with immediate postoperative values (p<0.05). The perfusion was significantly decreased in proximal areas at day 1, and in distal areas at day 1 to 7 in both ischemia control and IL‐10 and BMSCs groups compared with Sham (p<0.05). There was a modest increment in blood perfusion in both proximal and distal areas of IL‐10 and BMSCs groups compared to the Ischemia control.ConclusionIL‐10 participated and contributed the protective effect to the animal model of cutaneous flap subjected to IRI.Support or Funding InformationSupported by a Malcolm Feist Postdoctoral Fellowship
Evaluation of Sex Differences in Vascular Density in a Rodent Model of Traumatic Brain Injury Using Steady‐State Contrast Enhanced Magnetic Resonance Imaging
Authors: Mayo Jamie Nadine , Wright David , Phillips Roree , O'Brien Terence J. , Shultz Sandy 
Published: November 2023

ObjectiveThe mechanisms by which female rats fare better then male rats post‐TBI remain unclear. Changes in vascular density and other measures of new blood vessel growth, angiogenesis, play a role in recovery post‐TBI. Vascular function has been hypothesized to be involved in sex differences in recovery post‐TBI. It is unknown if there are sex differences in injury induced changes in vessel density post‐TBI. The hypothesis was tested that females would have greater vessel density 48 hours post‐TBI than males, and that they would outperform males on motor coordination tasks one week after injury.MethodsAdult male and female rats were subjected to a severe TBI using a fluid percussion injury model. Steady‐state contrast enhanced MRI (SSC‐MRI, 15 mg/kg of ferumoxytol) was used to assess injured cortex vessel density in vivo 48 hours post‐injury. Motor coordination was assessed one week post‐injury using the balance beam.ResultsInjury and sex were a significant source of variation (p < 0.05) in regards to motor coordination performance. Injured male rats had a 2.4‐fold increase in beam traversal time (p < 0.05) as compared to male shams. No statistical difference was found between injured and sham females (p > 0.05). In regards to the SSC‐MRI results, 48 hours post‐ injury both sex and injury were a significant source of variation in vessel density within the ipsilateral cortex (p < 0.05). Injured males had a 0.84 fold decrease in vessel density as compared to male shams (p < 0.05). Injured females did not have a significant difference in vessel density as compared to female shams (p > 0.05).ConclusionsThe greater vessel density in injured females as compared to injured males may contribute to sex differences in motor coordination post‐TBI. SSC‐MRI could be used in future clinical studies in order to elucidate the temporal changes in cortical vessel density post‐TBI. A better understanding of sex differences in vascular responses post‐injury could aide in ensuring that the development of therapies targeting angiogenesis post‐TBI will be appropriate for both male and female patients.
Recovery of Vasomotor Control in Microvascular Resistance Networks of Regenerating Skeletal Muscle
Authors: Fernando Charmain A , Cornelison D W , Segal Steven S 
Published: November 2023

The microcirculation is disrupted during degeneration of injured skeletal muscle (skm). While regeneration of skm fibers is well studied, little is known about recovery of the microcirculation during skm regeneration. Our working hypothesis is that restoration of microvascular structure and function is integral to skm regeneration. In anesthetized male C57BL/6J mice (4 months, n=4/group), the gluteus maximus muscle (GM) was injured by local injection of barium chloride solution (1.2%), causing degeneration/regeneration of affected muscle fibers. At 5 days (d) post‐injury (PI), microvascular perfusion was restored as determined by intravital imaging of fluorescent plasma (FITC‐dextran, 70 kDa) in the regenerating GM. Functional integrity of the resistance network was evaluated at 5, 10 and 21d PI vs control by measuring internal diameter (ID) of feed arteries (FA), first‐ (1A), second‐ (2A) and third‐order (3A) arterioles supplying the GM. Maximal IDs (topical sodium nitroprusside, 10−4 M) decreased as branch order increased (P<0.05) but were not different across time points within each branch order. Resting IDs of all branch orders were greater (P<0.05) than control at 5d and 10d PI, particularly in FA and 1A, then recovered to control by 21d, as did spontaneous tone. At each time point, responses to increasing agonist concentration were evaluated from 10−9 to 10−5 M. Vasoconstriction to α1‐adrenoreceptor (AR) stimulation (phenylephrine) was attenuated at 5d across branch orders and recovered to control by 21d. Vasoconstriction to α2AR stimulation (UK14304) was ~50% less (P<0.05) than to α1AR stimulation and was not different across respective time points vs control. Vasodilation to acetylcholine was negligible at 5d and increased progressively at 10d and 21d PI (P<0.05) for all branch orders, with greatest efficacy in 3A. Thus myogenic tone and smooth muscle reactivity to α1AR stimulation recover in parallel while endothelium‐dependent vasodilation recovers progressively through 21d PI. Resolving the time course for restoration of vasomotor control in regenerating skm provides novel perspective towards developing therapeutic strategies for restoring skm function during recovery from injury.Support or Funding InformationMulligan Professorship, NIH RO1AR067450, NIH R37HL041026
Exercise Recovers Loss of Microvessel Density due to Lowered Nitric Oxide Bioavailability
Authors: Branyan Kayla , Ashman Melissa , Pitzer Christopher , Chantler Paul , Olfert Mark 
Published: November 2023

Microvessel rarefaction is an indicator of a challenged or disease state in both humans and animal models. The loss of peripheral microvessel density is associated with the metabolic syndrome (MetS). Decreased microvessel density significantly increases the risk for vascular dysfunction and peripheral vascular disease (PVD). Nitric oxide (NO) has been shown to have pro‐angiogenic properties, which suggests that improvement of NO bioavailability in MetS can augment microvessel rarefaction. Exercise, when used as an intervention during MetS, can improve NO bioavailability. The initiating factors for microvessel rarefaction still remain unclear and whether or not exercise can reverse the rarefaction associated with MetS needs to be determined. To examine the correlation between loss in microvessel density and decrease in nitric oxide (NO) bioavailability, capillary to fiber ratio was measured in the soleus and gracilis muscles of obese Zucker rats (OZRs), a model of MetS, and in lean healthy Zucker rats (LZRs). NO levels were measured in stimulated aortas of both groups. OZRs and LZRs were separated into sedentary and exercise training groups (consisting of treadmill running 1 hr/d, 5 d/wk for 8 weeks at 70% of their max running speed). The gracilis arteriole was isolated and then cannulated in a pressurized vessel myobath and exposed to increasing doses of acetylcholine (ACh) to test endothelium‐dependent dilation. Capillary density in the soleus was significantly lower by 15% in OZRs compared to LZRs (p<0.05), and exercise training did not have an effect. In the gracilis, exercise improved capillary density in both OZRs and LZRs. The difference in capillary density between OZR and LZR controls in the gracilis suggest a genotypic disparity. NO bioavailability was significantly decreased in sedentary OZR compared to sedentary LZR, and exercise augmented NO in both groups (p<0.05). Gracilis arteriole dilation response was lower in OZR than LZR (p<0.01) but exercise improved dilation in OZR to almost LZR control values. These results suggest that there is a correlation between decreased NO bioavailability and the loss of peripheral microvessel density, and that exercise may at least partially, depending on the muscle type, reverse this effect and recover arteriole reactivity.Support or Funding InformationThe authors gratefully acknowledge the support by National Institute of Health (5P20GM109098)
IGF‐1 Receptor on Leukocytes Potentiates Western Diet‐induced Inflammatory Response and Progression of Atherosclerosis in ApoE‐Deficient Mice
Authors: Wang Meifang , Higashi Yusuke , Wang Derek , Yu Hong , Delafontaine Patrice , Korthuis Ronald 
Published: November 2023

Atherosclerosis is the principal underlying cause of most cardiovascular disease‐related deaths, the leading cause of mortality in the US. Insulin‐like growth factor‐1 (IGF‐1), the primary mediator of the effect of growth hormone on developmental growth, is expressed in vascular cells and monocytes/macrophages. However, IGF‐1's role in atherosclerosis is unknown. Our previous studies showed that lowered circulating IGF‐1 increases atherosclerosis progression in atherosclerosis‐prone apolipoprotein E‐deficient mice (ApoE−/−) while increased circulating IGF‐1 downregulates expression of vascular pro‐inflammatory cytokines, reduces systemic and vascular oxidant stress, and decreases atherosclerosis progression. We also demonstrated that that the aforementioned inflammatory phenotype is potentiated in mice with double knockout of ApoE and IGF1 receptor (IGF1R), where IGF1R expression was selectively deleted in monocyte/macrophages (ApoE−/− LC), and that consumption of a Western diet enhanced monocyte‐endothelial interactions in these double knockout mice compared to wild type IGF‐1R/ApoE−/−‐flox mice (ApoE−/−‐FIR). Here, we examined similar endpoints in an ApoE/IGFR1−/− model in which IGF1R‐expression was selectively deleted in endothelial cells (ApoE−/− VF), and again examined the possible interaction of the effect of these knockouts with consumption of a Western diet, comparing ApoE−/− VF with IGF‐1R ApoE−/−‐flox mice (ApoE−/−‐FIR). We compared baseline Leukocyte Rolling (LR) and Leukocyte Adhesion (LA) in both these mice fed either normal mouse chow (NC) or Western diet (WD). There was significant increase in the pro‐inflammatory phenotype in both NC fed mice (ApoE−/− VF NC and ApoE−/−‐FIR NC) compared to C57BL6 wild type mice. Ingestion of a Western Diet markedly enhanced LR and LA on both ApoE−/− VF animals (ApoE−/− VF WD) and ApoE−/− ‐FIR animals (ApoE−/− ‐FIR WD), however. This finding indicates that the pro‐inflammatory phenotype enhanced by WD in ApoE−/− VF and FIR mice is not further enhanced by specific IGF1R deficiency in endothelial cells. We conclude that IGF‐1 receptor on leukocytes, but not endothelial cells, potentiates the inflammatory phenotype induced by Western Diet in ApoE‐deficient mice.Support or Funding InformationSupported by NIH: R01‐HL59976, RO1 HL070241 and HL 080682, R01‐AA22108.
Interleukin‐12 Disruption Protects Myocardium from Ischemia‐Reperfusion Injury in Type 2 Diabetic Mice
Authors: Mali Vishal , Tennant Will , Haddox Samuel , Matrougui Khalid , Belmadani Souad 
Published: November 2023

IntroductionMyocardial infarction (MI) is the most common cause of mortality in diabetes. In the present study, we determined the in vivo role and mechanism for interleukin‐12 (IL‐12) in myocardial infarction in type 2 diabetic mice.Methods and ResultsC57/Bl6, IL‐12−/−, db−/db−, and db−/db−IL‐12−/− were subjected to myocardial ischemia for 40 minutes and followed by reperfusion (I/R) injury for 24 hours. I/R injury induces a significant myocardial infarct in C57/Bl6 but substantially greater in db−/db− mice. Interestingly, IL‐12−/− and db−/db−IL‐12−/− are protected against I/R injury as indicated by the small infarct size. The IL‐12 disruption protective effect involves endoplasmic reticulum (ER) stress, inflammation, AMPKinase and Akt signaling. Thus, phosphorylated AMPKinase and Akt were enhanced in the heart from IL‐12−/− and db−/db−IL‐12−/− mice subjected to I/R injury compared to C57/Bl6 and db−/db− subjected to I/R injury. Moreover, after I/R injury, inflammation, assessed by the infiltration of macrophages and leukocytes into the heart, and ER stress CHOP were reduced in IL‐12−/− and db−/db−IL‐12−/− compared to C57/Bl6 and db−/db− mice.ConclusionThe present study highlighted the in vivo essential role for IL‐12 disruption in the cardio‐protection against I/R injury in type 2 diabetes. The protective mechanism of IL‐12 disruption involves ER stress, inflammation, AMPKinase, and Akt pathways.
Cathepsin B Mediated Degradation of Jejunal Epithelial Tight Junction Proteins during the Early Stage of Hemorrhagic Shock
Authors: Klein Nikolas Philipp , Courelli Asimina , Schmid‐Schoenbein Geert 
Published: November 2023

Hemorrhagic shock has been strongly linked to intestinal permeability — a hallmark of intestinal epithelial barrier breakdown — whose increase is associated with reduced function of intercellular adhesion proteins. The early effects of hemorrhagic shock (HS) on junctional epithelial proteins and the potential mechanisms of increased intestinal permeability have not been fully investigated. We investigate three junctional proteins responsible for epithelial cell adhesion in the jejunum: Claudin‐3, Occludin, and E‐Cadherin. We also investigate the role of Cathepsin B, an epithelial lysosomal cysteine protease, in the degradation of those adhesion protein. We hypothesize that Cathepsin B cleaves the extracellular domain of the adhesion molecules in HS. 16 Sprague‐Dawley rats were divided into 4 groups of 4 animals: Control, HS (MAP = 35mmHg for 30 min without blood volume reconstitution), HS with enteral pre‐treatment by Golytely as a fluid carrier, and HS with enteral pre‐treatment by Golytely and CA074 (Cathepsin B inhibitor at 15mg/kg). Jejunum was collected for Western Blot and immunohistochemistry of Claudin‐3, Occludin, and E‐Cadherin. Both Western Blot and immunohistochemistry results showed a decrease in levels of Claudin‐3 (HS p‐value: 0.052; HS with Golytely p‐value: 0.026), Occludin (HS p‐value: 0.011; HS with Golytely p‐value: 0.0036), and E‐Cadherin (HS p‐value: 0.013; HS with Golytely p‐value: 0.00137) in HS and HS pretreated with Golytely groups when compared to Control. Addition of Cathepsin B inhibitor resulted in maintenance of junctional proteins in the jejunum after HS. These results indicate that active Cathepsin B is released early during HS and causes a reduction of cell‐cell adhesion proteins Claudin‐3, Occludin, and E‐Cadherin, leading to increased intestinal permeability.Support or Funding InformationNIH Grant: GM 85072
Chloropalmitate increases solute permeability and VE‐cadherin internalization in human microvascular endothelial cells
Authors: Kalogeris Theodore , Birkhead Travis Michael , Ford David , Korthuis Ronald 
Published: November 2023

Chlorinating species generated through the activity of neutrophil/macrophage myeloperoxidase have been found to produce various types of chlorinated lipids under inflammatory conditions, and these lipids In turn have been implicated as potential contributing factors in the inflammatory phenotype seen after ischemia/reperfusion. In previous studies in cultured microvascular endothelial cells, we documented increases in cortical stiffness and cytoskeletal reorganization in cells exposed to chloro‐palmitate. In the present studies we examined whether chlorolipids could also affect endothelial barrier function. Human microvascular endothelial cells (HMEC‐1) grown to confluence on 0.4 μm transwell inserts were incubated with 2‐chlorohexadecanal (chloro‐fatty palmitaldehyde, Cl‐HDA) or 2‐chlorohexadecanic acid (chloro‐palmitate, CL‐FA), or their non‐chlorinated lipid precursors as controls, and the permeability of the monolayer to FITC‐albumin was calculated from measured albumin flux and transwell albumin concentration gradient using Fick's law. Compared with control treatments (palmitate, ethanol [vehicle]), Cl‐FA produced a 3–4‐fold increase in permeability which persisted over at least 4 h, similar to the permeability effect of the positive control agent, TNFα, while Cl‐HDA's effect was not significantly different from control. In followup studies, we examined the effect of the aforementioned treatments on VE‐cadherin distribution using a trypsin‐protection assay. Treatment with Cl‐FA or Cl‐HDA protected cell surface VE‐cadherin from trypsin‐induced degradation, consistent with chlorolipid‐induced VE‐cadherin internalization. These data support the hypothesis that Cl‐FA induces endothelial barrier dysfunction associated with increased cell stiffness, and reorganization of the cortical cytoskeleton and adherens junctions. Our results also suggest a dissociation between adherens junction integrity and permeability in the case of Cl‐HDA.Support or Funding InformationN.I.H. GM‐115553, AA‐22108
Cardioprotective effects of hydroalcoholic extract of Terminalia capatta in isolated perfused rat hearts.
Authors: Torres‐Tirado Jose David , Pérez Gabriela , Sanchez Eugenia , Estrada Alejandro , Zacarias Alejandra , Leon Angel 
Published: November 2023

The use of traditional medicinal plants in prevention and treatment of different illnesses is a comun practice in the world. Mexico has a long traditional plants applications since ancient times. Terminalia catappa is used in the empirical treatment of skin illness, digestive diseases and in a recent study the seed extract show cardio protective effects. The aim of this work was to test the cardioprotective effect of hydroalcoholic extract of Terminalia capatta leaves. The extract was oral administrated one time a day in wistar rats during seven days after its were sacrificed to test ten min ischemia and ten min reperfusion in Langendorff isolated heart technique. Results showed an important decrease in loss of contraction of the left ventricular pressure of 20 % vs control. The histology showed an 16% decrease in the infarct size vs control. Terminalia capatta extract showed an important cardioprotective effects in our model.Support or Funding InformationThis work was supported by grants from UASLP (FAI 2014 to JTT and 2016 to GP)
Calreticulin localized to the myoendothelial junction mediates heterocellular communication in resistance arteries
Authors: Biwer Lauren A , Good Miranda E , Hong Kwangseok , Patel Rahul , Agrawal Neha , Looft‐Wilson Robin , Sonkusare Swapnil , Isakson Brant E 
Published: November 2023

Regulated heterocellular communication depends on bidirectional signaling that occurs at myoendothelial junctions (MEJs), which are composed of endothelial cell (EC) extensions that make direct cytoplasmic contact with smooth muscle cells (SMC). The MEJ is the anatomical hallmark of resistance arteries and is a key signaling microdomain with endoplasmic reticulum (ER) as we demonstrate via expression of the ER retention signal –KDEL, and ER tracker in a live artery, both of which localize to holes in the internal elastic lamina. Presumably, the expression of ER in the MEJ could facilitate localized Ca2+ events at MEJs generated in response to second messengers from EC agonists or smooth muscle (SMC) agonists (by movement of IP3 or Ca2+ through gap junctions to the EC extensions composing MEJs). To determine what proteins may regulate the spatially localized Ca2+ events at the MEJ, we used an iTRAQ proteomic screen on in vitro MEJs and found significant enrichment of calreticulin. Calreticulin is a calcium binding protein that has been shown to bind ~50% of ER calcium. We confirmed the presence of calreticulin at MEJs using third‐order mesenteric arterioles. Thus, we hypothesized that deletion of EC calreticulin could alter Ca2+ events at the MEJ that were generated after application of EC or SMC agonists. For this reason we created an EC specific calreticulin conditional knockout mouse (Calreticulinfl/fl/CDH5‐CreERT2+). Initial experiments were performed in mice between 10–20 weeks old. In these experiments, carbachol (CCH; EC specific) or phenylephrine (PE; SMC specific) was added to third order mesenteric arteries and the Ca2+ events were quantified. The control mice had a robust increase in Ca2+ events at MEJs after PE stimulation, but Calreticulinfl/fl/CDH5‐CreERT2+ mice had a significantly reduced number of Ca2+ events. Furthermore, Calreticulinfl/fl/CDH5‐CreERT2+ mice had significantly enhanced constriction to PE, demonstrating the importance of calreticulin at the MEJ in the PE response. Conversely, CCH stimulation showed no differences in Ca2+ events and no difference in dilation to CCH in the Calreticulinfl/fl/CDH5‐CreERT2+ mouse. This polarized response in Ca2+ events at MEJs in Calreticulinfl/fl/CDH5‐CreERT2+ endothelium was lost in mice aged >75 weeks. These results demonstrate: 1) the enrichment of calreticulin to MEJs, 2) polarized activation of EC Ca2+ events is based upon whether the agonist is EC (apical) or SMC (MEJ) in origin and 3) aging alters how calreticulin polarizes Ca2+ events after agonist stimulation. Overall, we believe EC calreticulin can regulate Ca2+ events generated in responses to heterocellular communication.Support or Funding InformationNational Institutes of Health HL088554, HL120840, T32 HL007284, and American HeartAssociation 14PRE20420024