bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increase in cerebrovascular permeability leads to fibrinogen‐cellular prion protein complex formation after traumatic brain injury (672.1)
Authors: Muradashvili Nino , Tyagi Reeta , Benton Richard , Tyagi Suresh , Lominadze David 
Published: June 2021

Traumatic brain injury (TBI) is the most common cause of death and disability. It is accompanied with development of inflammation and thus linked to increased content of inflammatory mediators including fibrinogen (Fg). It is known that TBI is associated with loss of memory that can be affected by the level of cellular prion protein (PrPC).We tested the hypothesis that TBI‐induced an increase in cerebrovascular permeability leads to Fg exstravasation in pericontusional area through activation of MMP‐9. Deposited Fg contributes to formation of Fg‐PrPC complex and can be related to loss of short‐term memory.Pial venular leakage was observed by intravital fluorescence microscopy in male wild‐type (WT, C57BL/6J) and MMP‐9 gene knockout (MMP9‐/‐) mice after TBI. Fg deposition and formation of Fg‐PrPC complex were assessed by immunohistochemistry. Short‐term memory of mice was estimated by a novel object recognition test.Cerebrovascular leakage, Fg deposition, and it’s co‐localization with PrPC were increased after TBI in each experimental group compared to those in respective sham‐operated mice. However, they were greater in WT than in MMP9‐/‐ mice.Thus, our data suggest that TBI‐induced increased cerebrovascular permeability and the resultant Fg deposition leads to Fg‐PrPC complex formation. The latter can be involved in loss of memory. These results indicate a novel role of Fg in post‐TBI pathology.Grant Funding Source: NIH P30 GM103507 and NS084823
Atrial natriuretic peptide attenuates thrombin‐induced inflammation (672.4)
Authors: Curry Fitz‐Roy , Jiang Yan , Kim Min‐Ho , Clark Joyce , Adamson Roger , Simon Scott 
Published: June 2021

One microcirculatory homeostatic action of atrial natriuretic peptide (ANP) in the absence of inflammation is to increase barrier permeability to plasma proteins (Ps) when plasma volume is increased. However several investigations, particularly in cultured endothelial cells, suggest that high concentrations of ANP may also attenuate Ps. We tested the hypothesis that this action of ANP was characteristic of endothelium expressing a pro‐inflammatory phenotype. In individually perfused rat mesentery microvessels with no prior exposure to inflammation, pretreatment for 30 min with ANP (100 ng/ml) did not attenuate the increased permeability after exposure to bradykinin (10 nM). However in mouse skin where thrombin increased Ps 24 hours after an aseptic wound (AJP Heart, 296: 848, 2009), ANP added to the wound (50 ng/min/kg bw) significantly attenuated the thrombin induced transvascular albumin. At the same time, ANP attenuated thrombin induced neutrophil accumulation in the wound, and ANP alone increased Ps. Our results confirm that ANP acts to attenuate transvascular exchange in an intact microvasculature but only under inflammatory conditions. The mechanism of action appears to be independent of the normal ANP signaling pathways to increase Ps, and may involve reduced production of pro‐inflammatory agents from activated endothelium, neutrophils, or other inflammatory cells.Grant Funding Source: Supported by NIH HL28607
Variable roles of the H1‐H3 receptors and PKC in histamine‐induced barrier dysfunction in cultured endothelial cells from different sources (672.6)
Authors: Adderley Shaquria , Zhang Xun , Sarangan Sandhya , Breslin Jerome 
Published: June 2021

We tested the hypothesis that histamine‐induced endothelial barrier dysfunction requires different receptors and signaling pathways depending upon endothelial cell (EC) source. Changes in barrier function elicited by 10 μM histamine were compared between human umbilical vein EC (HUVEC) and human dermal microvascular EC (HMVEC‐D) monolayers, using determination of transendothelial electrical resistance (TER). H1, H2, and H3 receptors were blocked with 10 μM mepyramine, 10 μM cimetidine, and 0.01‐1 μM ciproxifan, respectively. Inhibitors of PKC (GFX109203X), PI3K (PI828) and phospholipase C (U73122) were used to evaluate downstream signals. Western blots and immunofluorescence microscopy analysis demonstrated H1, H2, and H3 expression in both EC types. Blockade of H1, H2, or H3 significantly inhibited the histamine‐induced decrease in TER in HMVEC‐D. In contrast, only blockade of H1 significantly attenuated the histamine‐induced drop in TER in HUVEC. Inhibition of either PKC or PI3K significantly attenuated histamine‐induced barrier dysfunction in HUVEC, but combined inhibition of both was required to attain significant attenuation in HMVEC‐D. Inhibition of PLC also inhibited the histamine‐induced decrease in TER in HMVEC‐D, but interestingly, combined PLC and PKC inhibition did not. This study suggests a common role for H1, but differential roles for H2 and H3 in histamine‐induced endothelial barrier dysfunction among different endothelial cell types. In addition, PKC appears to have either a promoting or inhibitory role depending on the endothelial cell source. Supported by NIH R01HL098215.Grant Funding Source: NIH R01HL098215
Computational analyses of oxygen transport suggest that perfusion heterogeneity, not overall oxygen delivery, limits muscle performance in metabolic syndrome (674.7)
Authors: Frisbee Jefferson , Wu Fan 
Published: June 2021

The ability of in situ skeletal muscle to perform is compromised with development of metabolic syndrome in obese Zucker rats (OZR); a model of vascular disease without atherosclerosis. At 17 weeks, skeletal muscle function appears to be normal, implicating the microcirculation as a major contributor to poor performance; yet actual contributors to this are unclear. We performed computational analyses on single capillary O2 transport in LZR and OZR, using the Krogh model to compute axial PO2 distribution given metabolic rate and capillary diameter. The target variable is ΔPO2 between the capillary center and outer wall of a tissue cylinder. Initial analyses suggest that, assuming uniform microvascular perfusion, the maximum axial ΔPO2 is 13 mmHg in LZR and 10 mmHg in OZR at fatiguing contractions, suggesting that oxygenation in both is sufficient to support metabolism and that O2 consumption is not limited by bulk perfusion in LZR or OZR. Combined with our previous findings on capillary‐level flow distributions [Wu et al., 2011], this implies that increased muscle fatigue in OZR is associated with heterogeneous flow distribution, causing local mismatch between O2 supply and metabolic demand.Grant Funding Source: Supported by National Institutes of Health and American Heart Association
Comparison of plasma and 5% albumin resuscitation on preserving endothelial glycocalyx and microvascular permeability in vivo after severe hemorrhagic shock in rats (676.12)
Authors: Torres Luciana , Sondeen Jill , Salgado Christi , Dubick Michael , Torres Filho Ivo 
Published: June 2021

Plasma expanders have been used to promote volume replacement and improve hemodynamics and tissue perfusion after HS. We have investigated the effects of high viscosity plasma expanders on the EG of cremaster muscle venules from anesthetized rats subjected to 40% HS for 1h followed by 1h resuscitation with 5% albumin (ALB, Buminate), fresh frozen plasma (FFP) or 6% Hetastarch (HEX, Hextend). EG thickness, blood flow, and permeability were studied using intravital microscopy. Hemodynamics and coagulation tests (ROTEM) were measured. Mean arterial pressure was significantly lower than baseline for all groups (hypotensive resuscitation). HEX group showed significantly lower EG thickness, higher blood flow and permeability than the FFP. ALB partially restored EG thickness (80% of baseline), but showed higher blood flow and shear rate than the FFP group (p<0.05). Permeability was 20% higher in the ALB group than baseline. EXTEM and FIBTEM showed higher clotting time and lower clot strength in the ALB and HEX groups compared to FFP. In conclusion, resuscitation with ALB alone is not sufficient to return the EG thickness, permeability and coagulation to normal after HS possibly due to the lack of other plasma components beyond that of albumin. Resuscitation with FFP is superior to high viscosity plasma expanders, including the main FFP protein constituent alone.Supported by US Army Medical Research & Materiel Command.
Vasopressin receptor 2 stimulation increases permeability in human microvascular endothelial cells (676.16)
Authors: Lopez Ernesto , Fujiwara Osamu , Zhu Yong , Enkhbaatar Perenlei 
Published: June 2021

Introduction: Arginine vasopressin (AVP) is administered in sepsis to increase arterial pressure by activating AVP receptor 1 (V1R). Limited attention has been given to effects of AVP receptor 2 (V2R) on endothelial cells. Previously, in our ovine model of sepsis, we have reported that treatment of severe sepsis with V1R selective agonist prevents vascular hyper‐permeability as compared to animals treated with non‐selective AVP. We hypothesize that V2R activation is critically involved in the pathogenesis of vascular hyper‐permeability, which is a severe complication of sepsis.Methods: An electrical impedance assay was adapted to assess acute changes of connectivity in confluent Human Lung Microvascular Endothelial Cells (HMVECs). Confluent cells were exposed to different doses of V2R specific agonist, Desmopressin (DDAVP), Vascular Endothelial Growth Factor (VEGF) or vehicle. The intercellular connectivity (electrical impedance) was measured every 15 min during 24 hours (h). A HMVECs permeability assay was also performed measuring the amount of FITC‐dextran passing through the endothelial monolayer after 18 h of treatment with DDAVP or VEGF.Results: V2R expression in HMVECs was verified with RT‐PCR. DDAVP caused a decrease of HMVECs connectivity with a maximum difference at 0.5 h of treatment. Its clear dose dependent effect was also seen at 0.5 h with 0.3nM, 1nM, 3nM (p蠄0.05), 10nM (p蠄0.0001), and 30nM (p蠄0.0001). The effect was similar to changes seen with 3 ng/ml VEGF (p蠄0.0001), but milder than 10 ng/ml VEGF. The changes in HMVECs connectivity remained during the rest of the experiment. The FITC‐dextran permeability assay also showed a trend of increased permeability with 10 nM DDAVP and 50 ng/ml VEGF.Conclusions: These results suggest that the activation of V2R disrupts the endothelial barrier within minutes, thus causing hyper‐permeability. Additional studies are being performed in our in vivo model to elucidate the role of V2R in sepsis induced vascular hyper‐permeability.Grant Funding Source: Supported by NIH RO1 GM097480, SHC85500, SHC84050 and CONACYT‐Mexico
Pre‐diabetes promotes sympathetically‐mediated arteriolar dysregulation in response to skeletal muscle contraction (676.20)
Authors: Novielli Nicole , Medeiros Philip , Jackson Dwayne 
Published: June 2021

Augmented sympathetic vascular regulation is associated with pre‐diabetes, thus it may contribute to impaired contraction‐evoked arteriolar dilation in skeletal muscle, previously demonstrated by our group. Thus we tested the hypothesis that blunted contraction‐evoked arteriolar dilation in pre‐diabetes occurs as a result of augmented sympathetic neuropeptide Y1 receptor (NPY Y1R) and α1 adrenergic receptor (α1R) control. Using intravital video microscopy, second‐ third‐ and fourth‐order arteriolar diameter changes were measured in response to electrical field stimulation of the gluteus maximus muscle in pre‐diabetic (PD, Pound Mouse, n=6‐13) and control (CTRL, c57bl6, CTRL, n=5‐12) mice. Baseline diameter was similar between groups, however vasodilatory responses to single tetanic (100Hz; 400 and 800ms) and sustained rhythmic (2 and 8Hz; 30s) contractions were blunted by 50% or greater in PD versus CTRL (p<0.05). In line with our hypothesis, decrements in contraction‐evoked dilation in PD were restored upon Y1R and α1R blockade (BIBP3226 and prazosin, 100nM). Arteriolar reactivity (% change from baseline diameter) to muscle contraction was greatest at distal arterioles in CTRL. Such spatial differences in arteriolar reactivity were absent in PD, but were restored with Y1R and α1R blockade. Finally, arteriolar vasoconstrictor responses to increasing doses of NPY (10‐13 ‐ 10‐8 M) or PE (10‐9 M ‐ 10‐5 M) were greater in PD versus CTRL, an observation that was consistent with greater Y1R and α1R expression in isolated arterioles and vascular smooth muscle cells in PD. Deficits in contraction‐evoked arteriolar dilation in this model of pre‐diabetes are a result of elevated sympathetic arteriolar Y1R and α1R expression and activation.Grant Funding Source: NSERC
Potassium and calcium channel gene expression in small arteries in porcine and rat models of diet‐induced obesity (676.4)
Authors: Jensen Lars , Salomonson Max , Sorensen Charlotte , Holstein‐Rathlou Niels‐Henrik , Pedersen Henrik , Christoffersen Berit , Olsen Lisbeth , Ludvigsen Trine 
Published: June 2021

Obesity is an increasing problem worldwide leading to cardiovascular morbidity. Only limited information exists on the transcriptional regulation of arterial K+ and Ca2+ channels in obesity. We quantified, by real‐time PCR, mRNA expression of K+ channels and L‐type Ca2+ channels (LTCC) in small mesenteric (MA), middle cerebral (MCA), and left coronary arteries (LCA) of lean vs. obese rats and minipigs. Male Sprague Dawley rats were fed a high‐fat (FAT; N=5), high‐fructose (FRUC; N=7), high‐fat/high‐fructose (FAT/FRUC; N=7) or standard diet (STD; N=7‐11) for 28 Weeks. FAT and FAT/FRUC became obese, whereas FRUC and STD were lean. Systolic blood pressure (SBP) averaged over 14 weeks was increased (P<0.001) in FRUC and FAT/FRUC but not in FAT. Kir, Kv1.2, Kv1.5, and Kv7.4 channels were up‐regulated in FAT, whereas SKca and IKca channels were down‐regulated in FAT/FRUC (P<0.05). There were no transcriptional changes in FRUC. Castrated male Göttingen minipigs with or without diabetes were fed a diet rich in fat, cholesterol and fructose (OB+DIAB; N=3 vs. OB; N=2, respectively) or a standard diet (STD; N=3) for 22‐45 weeks. Body weight, total body fat content and plasma triglyceride levels were increased in OB and OB+DIAB. BKca, IKca, SKca and/or LTCC mRNA was up‐regulated in LCA from OB and OB+DIAB (n.s.). Expression of BKca mRNA was increased, whereas IKca mRNA decreased in MCA from OB (n.s.). SKca mRNA was decreased in MA from OB (n.s.). Diet‐induced obesity in rats and minipigs lead to complex changes in K+ and Ca2+ channel gene expression, which, in rats, did not seem to be linked with changes in SBP. These transcriptional changes may lead to disturbances in microvascular flow patterns in obesity.Grant Funding Source: Supported by: Danish Medical Research Council; The Foundation for the Advancement of Medical Science
Sildenafil improves cardiovascular function in experimental hypertension (676.5)
Authors: Balarini Camille , Dias Ananda , Fahning Bernah , Cintra Amanda , Frossard Jessica , Gomes Isabele , Gava Agata , Meyrelles Silvana , Vasquez Elisardo 
Published: June 2021

The aim of the present study was to evaluate the beneficial cardiovascular effects of sildenafil treatment on experimental hypertension.Male C57BL/6 mice (n=5‐10) were subjected to 2K1C hypertension. After 14 days, sildenafil (40 mg/kg/day) or vehicle was administrated, during a period of 14 days. At the end of experimental period, animals were anesthetized and catheterized to blood pressure recording and had the mesenteric arteriolar bed removed to vascular function studies (acetylcholine ‐ ACh and norephrine ‐ Nor curves) (Protocol 02/2013‐ CEUA‐EMESCAM). Data are mean ± SEM. One‐way ANOVA was performed, followed by Tukey's post hoc test.*p<0.05 and **p<0.01 vs. 2K1C + vehicle. Sildenafil treatment reduced mean arterial blood pressure (124±2 vs. 112±3* mmHg) and heart rate (577±32 vs. 472±19* bpm) in hypertensive‐treated animals. Endothelial function was impaired in hypertensive animals and was successfully restored by sildenafil (Rmax ACh: 50.5±2% vs. 71.6±3%**). Blockage of nitric oxide production with L‐NAME revealed that the participation of this molecule in ACh‐induced vasodilation was augmented by sildenafil (AUC: 60.6±8 vs. 126.8±24*). Similarly, blockage with indomethacin showed the increased participation of COX‐derived prostanoids in vasodilation of treated animals (AUC: 37.9±9 vs. 95.9±17*). The participation of reactive oxygen species was evaluated by blockage of NADPH oxidase with apocinin and revealed that sildenafil was efficient in reducing oxidative stress (AUC: 94.±7.3 vs. 47.4±10.4*). Furthermore, sildenafil was also successful in reducing hyperactivity to Nor in 2K1C animals (Rmax: 167±8 vs. 117±9** mmHg). Thus, sildenafil can restore endothelial function and reduce blood pressure in experimental hypertension and could be suggested as a novel therapeutic approach while treating hypertensive patients.Grant Funding Source: Supported by: Fapes 54498465; CNPq 476525/2012‐8, 473082/2013‐6; FAPES/CNPq/PRONEX Edital 012/2009
The 3D structure of the myoendothelial projections: intracellular organelles, protein trafficking and biological function (677.12)
Authors: Maarouf Nadia , Welsh Donald 
Published: June 2021

The 3‐D structure of the myoendothelial projections: intracellular organelles, protein trafficking and biological Function Nadia Maarouf and Donald G. Welsh Department of physiology and pharmacology, University of Calgary, Calgary, AB, Canada Endothelial and smooth muscle cells communicate with one another in order to regulate vessel diameter. A key element of heterocellular communication is the myoendothelial projection, a thin endothelial extension that crosses the internal elastic lamina to make contact with the smooth muscle. The aim of this study was to ascertain the structural composition of the myoendothelial projection using electron tomography, a technique that enables the generation of 3‐D models. Anatomical models from mesenteric arteries reveal that myoendothelial projections are generally devoid of membranous structures, contrary to current thought. Intriguingly, key organelles such as endoplasmic reticulum with ribosomes, caveolae and vesicles were found in abundance at the base of the projection. The presence and positioning of the ribosomal endoplasmic reticulum suggests that in addition to governing Ca2+ regulation, this organelle contributes to protein packaging and trafficking to the plasma membrane which may include ion channels. In summary, the electron tomography approach provides valuable structural insight into the detailed composition of myoendothelial projections and their potential role in arterial tone regulation.Grant Funding Source: CIHR
Far red/near infrared light induces vasodilation and an increase in activity of large conductance potassium channel currents in murine femoral arterial muscle (677.13)
Authors: Lohr Nicole , Lindemer Brian , Harder David , Gebremendhin Debebe 
Published: June 2021

Over 8 million Americans are treated for symptoms related to peripheral artery disease (PAD), such as intermittent claudication, impaired wound healing, and critical limb ischemia. We have shown light irradiation at the far red/near infrared region (670 nm (R/NIR)) can stimulate angiogenesis by increasing NO independent of NOS through release of NO from nitrosyl‐heme stores. We hypothesized R/NIR can stimulate vasodilation through increases in large conductance potassium channel (BKCa) activity. To test vasodilation, facial arteries from C57Bl/6 mice were isolated, pressurized to 60mmHg, and pre‐constricted with U46619 in the dark.The vessels were irradiated with 670 nm light (10mW/cm2) up to 5 min at a time with 10 min dark period between irradiation. Vessel diameter increased up to 17.8% (±3.0, p<0.05) after 5 min of R/NIR exposure. The effect of red light on single channel BKCa current was determined in enzymatically dissociated murine femoral arterial muscle cells, using the patch clamp technique and symmetrical KCl [145mM] recording solution at a patch potential of +60 mV (RT). Exposure of cell attached patches to light ( λ =670 nm, 10 mW/cm2) markedly increased the opening frequency of the large conductance potassium channels (BKCa) single channel current. This effect of light on BKCa single channel current activity could be the underlying mechanism for the vasodilatory action of red light in isolated murine femoral arterial segments. Conclusion: R/NIR exposure acts to stimulate vasodilation, by increasing the opening frequency of BKCa single channel current recorded in cell attached patches of femoral arterial smooth muscle cells.
Acute effects of dietary bisphenol A on endothelial function in humans (677.14)
Authors: Chantler Paul , Casto Erica , DeVallance Evan , Fournier Sara , Fancher Ibra , Dick Gregory 
Published: June 2021

BPA is present in canned goods and detectable in the urine of >95% of US adults. Studies suggest a link between BPA and cardiovascular disease, but mechanistic information in human subjects is extremely limited. We investigated whether consuming 12‐oz of canned soup daily for 5 days would impair flow‐mediated dilation (FMD) of the brachial artery. FMD is an assay of endothelial function that provides insight into cardiovascular health. Using a double‐blinded crossover design, we compared the effects of 5 days of canned vs. fresh soup consumption in 7 healthy adults. The fresh soup recipes were matched for sodium and fat content, but contained no canned ingredients. After each week of soup, urinary BPA and FMD (with B‐mode ultrasound using published guidelines) were measured. Data were compared using paired t tests. BPA was undetectable in fresh soup (<0.01 ug/ml), but was 0.98 ± 0.72 ug/ml in canned soup. Thus a 12‐oz portion of canned soup could be expected to contain approximately 350 ug of BPA (representing a concentration of 4.4 uM). After a week of fresh soup, urinary BPA was 1.61 ± 0.48 ug/L. In contrast, after a week of canned soup, urinary BPA increased to 5.85 ± 4.87 ug/L (p < 0.05). However, FMD did not differ following a week of canned or fresh soup (10 ± 4 vs. 8 ± 2%, p = NS). These preliminary findings indicate that acute BPA consumption has little or no effect on endothelial function in healthy young individuals.Grant Funding Source: Supported by T32HL090610 and AHA 11CRP7370056
The vasoconstrictor agent phenylephrine selectively modulates endothelium‐ vs. smooth muscle‐mediated inhibition of myogenic tone in rat cremaster arteries (677.5)
Authors: Mishra Ramesh , Rahman Mohammad , Wulff Heike , Hill Michael , Braun Andrew 
Published: June 2021

The α1‐adrenergic agonist phenylephrine (PE) is reported to impact endothelium‐mediated vasorelaxation by influencing vasoactive signals transferred from endothelium to vascular smooth muscle (VSM), however, it is unclear whether this putative process occurs in myogenically active vessels at physiologic pressures. In the present study, we have examined the impact of PE and the TP receptor agonist U46619 on endothelium‐dependent and independent vasorelaxation of cannulated rat cremaster arterioles pressurized to 70 mmHg in the absence of luminal flow. Vasorelaxant agents acting via the endothelium (i.e. 0.3 μM acetylcholine (ACh) and 3 μM SKA‐31) or directly on VSM (i.e. 10 μM adenosine (ADO), 10 μM SNP, 5 μM pinacidil) reversibly inhibited myogenic tone by 50‐80%. Bath addition of 25 nM PE evoked a modest constriction on top of the existing myogenic tone, but did not alter the magnitude of vasorelaxant responses to ACh and SKA‐31. However, ADO‐mediated vasorelaxation was somewhat depressed and the response to pinacidil was enhanced. In the presence of U46619 (5 nM), no clear effects on either endothelium‐dependent or ‐independent vasodilatory stimuli were noted. In summary, the cellular pathways activated by PE and U46619 in VSM do not appear to influence endothelium‐mediated inhibition of myogenic tone in cremaster arterioles, suggesting that myo‐endothelial communication is unaffected by signaling events occurring downstream of α1‐adrenoceptor or TP receptor activation in these vessels.Grant Funding Source: Supported by CIHR