bluuebunny/crossref_metadata_2025_split huggingface dataset:
Administration of Prostacyclin Mediates Cutaneous Vasodilation but not Sweating in Young and Older Females: Roles for Nitric oxide and KCa channels
Authors: Fujii Naoto , McNeely Brendan D , Kenny Glen P 
Published: November 2023

Our recent report indicated that although prostacyclin does not mediate sweating in young and older males, it does modulate cutaneous vasodilation in both groups to a similar extent (Fujii et al. J Physiol 594 (21), 6419–6429, 2016). The same study also suggested that nitric oxide synthase (NOS) and calcium‐activated potassium (KCa) channels contribute to the prostacyclin‐induced cutaneous vasodilation in young males but, these contributions are diminished in older males. In our current study, we sought to evaluate whether the same responses are observed in young and older females. In young (25±4 years) and older (60±6 years) females (10 per group), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites: 1) Control, 2) 10 mM L‐NNA, a non‐specific NOS inhibitor, 3) 50 mM tetraethylammonium (TEA), a non‐specific KCa channel blocker, and 4) 10 mM L‐NNA + 50 mM TEA. All fours sites were co‐administered with prostacyclin in an incremental manner (0.04, 0.4, 4, 40, 400 μM each for 25 min). Our results demonstrated that both NOS and/or KCa channels contribute to prostacyclin‐induced cutaneous vasodilation for young and older females. This is based on our observations that the increased CVC due to prostacyclin administration was attenuated by TEA (0.4 μM) and a combination of L‐NNA and TEA (at all concentrations tested) in young females. Additionally, in older females the increased CVC due to prostacyclin administration was also reduced by separate administration of either L‐NNA or TEA (0.04–4 μM), and a combination of both agents (0.04–40 μM) (all P≤0.05). Surprisingly, increases in CVC in response to 0.04–4 μM prostacyclin were greater in older relative to young females (all P≤0.05), and these age‐related differences were diminished when both L‐NNA and TEA were simultaneously administered (all P>0.05). No effect on sweat rate was observed in either group (all concentrations, P>0.05). We conclude that while prostacyclin does not mediate sweating, it modulates cutaneous vasodilation to a greater extent in older relative to young females. Wherein, this modulation is likely due to NOS‐ and KCa channel‐dependent mechanisms.Support or Funding InformationThis study was supported by the Natural Sciences and Engineering Research Council of Canada (Discovery grant, RGPIN‐06313‐2014; Discovery Grants Program ‐ Accelerator Supplement, RGPAS‐462252‐2014). Funds held by Dr. Glen P. Kenny.
The Extracellular Matrix Proteoglycan Decorin is Upregulated by Endothelial Cells During Inflammation and Contributes to Blood‐Brain Barrier Dysfunction
Authors: Hoettels Brian A. , Wertz Travis S. , Birk David E. , Oxford Julie T. , Beard Richard S. 
Published: November 2023

The blood‐brain barrier (BBB) selectively regulates solute flux and protects the brain from bloodborne neurotoxic substances. Endothelial cells (ECs) forming the BBB establish highly restrictive cell‐cell contacts known as tight junctions (TJs), which aid in sealing paracellular clefts. The TJ protein claudin‐5 (CLDN5) is the primary constitutive protein responsible for the restriction of paracellular permeability to small molecules and the level of CLDN5 expression has been positively correlated with endothelial barrier tightness. Situated below the ECs is the extracellular matrix (ECM) which not only helps anchor the ECs, but also participates in ECM‐EC regulatory signaling. Under normal conditions, certain ECM proteins, such as collagens, have been shown to enhance the barrier properties of the BBB, whereas during inflammation other ECM proteins can contribute to BBB dysfunction, although the particulars of these mechanisms are still yet to be fully understood. In certain neuroinflammatory diseases, such as multiple sclerosis (MS), the upregulation of the ECM small leucine‐rich repeat proteoglycan (SLRP) decorin has been identified within the perivascular space of vessels in the inflammatory lesions of MS patients. The cellular origin of this decorin release and its potential impact on the BBB, however, has yet to be determined. In this study, we used murine models of inflammation in vivo and in vitro to determine a spatial‐temporal relationship between BBB dysfunction, CLDN5 loss, and increased decorin accumulation in the ECM. Consistent with the MS lesions, we identified increased decorin expression in mouse cerebellar microvessels post‐experimental autoimmune encephalomyelitis (EAE) induction as well as in primary brain microvascular endothelial cells (BMVECs) treated in vitro with inflammatory cytokines. Additionally, we evaluated the effect of different ECM‐EC interactions on CLDN5 expression and BMVEC monolayer integrity in vitro. Primary BMVECs cultivated on collagen‐coated surfaces showed a decrease in baseline solute permeability and increased CLDN5 expression compared to those on non‐coated surfaces, with those on collagen type IV‐coated surfaces showing a greater decrease in baseline permeability and CLDN5 expression compared to those on type I‐coated surfaces. However, surfaces containing decorin resulted in increased monolayer permeability and decreased CLDN5 expression, while matrices containing both decorin and type IV collagen resulted in abrogation of the observed enhancement of monolayer permeability and CLDN5 expression by type IV collagen. Taken together, our data suggest that ECs themselves may be the source of decorin accumulation in perivascular inflammatory lesions and that inflammatory‐induced decorin upregulation may perpetuate BBB dysfunction.Support or Funding InformationSupported by NIH P20 GM109095, 2P20GM103408.
Alterations to Venular Function in Skeletal Muscle with Metabolic Syndrome
Authors: Lemaster Kent , Farid Zahra , Jackson Dwayne , Goldman Daniel , Brock Robert , Frisbee Jefferson 
Published: November 2023

While the overwhelming majority of research into vascular outcomes of the metabolic syndrome have focused on the arterial/arteriolar and capillary levels, investigation into venular function and how development of metabolic syndrome impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR) as compared to control leans (LZR), we determined indices of venular network structure as well as vessel structure and function. At ~17 weeks of age, skeletal muscle post‐capillary venular density was reduced by ~20% in LZR vs. OZR, although there was no evidence of remodeling of the wall of individual venules impacting passive diameter. Initial basal diameter and blood flow within individual venules of ~25 mm and ~ 60 mm diameter was similar between LZR and OZR, although an increased variability was evident. Dilator responses to acetylcholine were consistently blunted in venules of OZR vs. LZR, and this reflected multiple effects: including an oxidant stress‐based loss of venular nitric oxide bioavailability, an increased constrictor tone from TxA2 and an increased constrictor tone mediated via the α1 adrenergic receptor. Impaired dilator responses were also coupled to vessels where increased leukocyte adhesion/rolling was clearly present. Venular constrictor responses between LZR and OZR were comparable for angiotensin II, endothelin and α2 adrenoreceptor stimulation, although responses to α1 adrenoreceptor stimulation were mildly elevated, but with increased variability. In response to field stimulation of the cremaster muscle (0.5 or 1/s, 400 ms duration, 60 Hz within train, 7V), venular dilator and hyperemic responses to contraction were blunted in OZR vs. LZR, but responses at the higher frequency were similar in magnitude. These results suggest that alterations in venular function may contribute to dysregulation of flow distribution in skeletal muscle with metabolic syndrome and impair parameters of mass transport and exchange.Support or Funding InformationNational Institutes of Health; American Heart Association
Polyethylene Glycol Camouflaged Earthworm Hemoglobin
Authors: Cabrales Pedro , Jani Vivek 
Published: November 2023

Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex of the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half‐life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG‐LtEc) can extend LtEc circulation time. This study explores PEG‐LtEc pharmacokinetics and pharmacodynamics. To study PEG‐LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG‐LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG‐LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG‐LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals' systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half‐life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG‐LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG‐LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc's already large molecular size. Taken together, these results further encourage the development of PEG‐LtEc as an O2 carrying therapeutic.Support or Funding InformationFunding: This work was supported by NIH grants from the Heart Lung and Blood Institute, P01‐HL110900, R56‐HL123015, and R01‐HL126945. Authors declare no competing financial interests.
Influence of Ischaemia‐Reperfusion Injury on the Subsequent Response to Local Heating in Non‐Glabrous and Glabrous Skin of the Index Finger
Authors: McGarr Gregory W. , Hodges Gary J. , Cheung Stephen S. 
Published: November 2023

Ischaemia‐reperfusion (I‐R) injury has been implicated in the pathophysiology of many clinical conditions including frostbite and non‐freezing cold injuries. The increased oxidative stress and inflammation associated with I‐R injury may contribute to impaired restoration of blood flow and tissue recovery in the hands and feet during rewarming through alterations in neurovascular and/or endothelial function. This may be reflected in an altered blood flow response to local skin heating, which is characterized by an initial vasodilatory peak that is primarily controlled by an axon reflex, followed by a secondary plateau that is influenced mainly by nitric oxide release from the endothelium. In ten participants we examined the responses to local heating in non‐glabrous and glabrous skin of the index finger following 20 minutes of ischaemia induced by inflating (220 mmHg) a standard blood pressure cuff around the arm and compared these with a time‐matched sham (non‐ischaemia) trial. Red blood cell flux, an index of skin blood flow, was examined using laser‐Doppler probes with integrated local heating units. Flux values were then divided by mean arterial pressure and reported as cutaneous vascular conductance (CVC). Local heating was initiated prior to ischaemia and 20 minutes after the release of cuff occlusion at separate skin sites. At each site local temperature was controlled at 33°C and then increased (3°C min−1) to 42°C and held for ~30 min. Following this, local temperature was increased to 44°C for 20 min. No changes were found in CVC for the initial peak and plateau phases or when heating to 44°C following ischaemia in either skin type (all P>0.05). However, the kinetics of the response were significantly altered by I‐R. Vasodilatory onset was delayed by 24% and 19% for non‐glabrous and glabrous skin, respectively (both P<0.05). Time to initial peak was also delayed by 17% and 11% in non‐glabrous and glabrous skin, respectively, although only the delay in non‐glabrous skin was significant (P<0.05). We conclude that 20 minutes of I‐R injury significantly impairs the kinetics of the response to a rapid, non‐painful local heating stimulus in both non‐glabrous and glabrous skin of the index finger, suggesting an alteration in neurovascular control. This delayed response may be associated with a higher temperature threshold for initiating vasodilation post‐ischaemia and could lead to persistent hypoxic stress during rapid rewarming in association with an increase in local skin temperature, coupled with insufficient tissue perfusion.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada: Discovery Grant (227912‐12, S.S. Cheung)
Human Skeletal Muscle Feed Artery Function: Role of the Advanced Glycation End‐Products Receptor (RAGE)
Authors: Park Soung Hun , Kwon Oh Sung , Andtbacka Robert H. I. , Hyngstrom John R. , Richardson Russell S. 
Published: November 2023

BackgroundAging is associated with impaired endothelium‐dependent dilation in human skeletal muscle feed arteries (SMFAs), vessels recognized to have regulatory function. Although growing evidence implicates RAGE in inflammation and endothelial dysfunction, the role of RAGE in human vascular function and blood flow regulation with advancing age is not well understood. Therefore, this study investigated the relative abundance of RAGE in the SMFAs from young and old humans and the relationship between RAGE abundance and SMFA vasodilatory function.MethodsRAGE protein expression was assessed in both young (28±4 yrs, n=6) and old (75±7 yrs, n=6) subjects with Western blot analysis. Endothelium‐dependent vasodilatory function was assessed in SMFAs, using pressure myography, in response to flow‐induced shear stress and acetylcholine (ACh). Endothelium‐independent vasodilatory function was assessed, in response to sodium nitroprusside (SNP).ResultsAn age‐related attenuation in endothelial‐dependent vasodilatory function was evident in response to flow (Young: 98 ± 15; Old: 30 ± 17%, P < 0.05) and ACh (Young: 98±10; Old: 61±13 %, P < 0.05), while the endothelial‐independent response to SNP was not affected by age. SMFA RAGE expression increased with age (p<0.05) and there was a significant negative correlation between RAGE protein expression and both flow (r2= −0.8783, P < 0.05) and ACh (r2= −0.7824, P < 0.05) induced vasodilation. There was no such relationship for RAGE and SNP induced vasodilation.ConclusionsThese findings imply that RAGE may play a critical role in the age‐related endothelial dysfunction documented in human SMFAs. Furthermore, this RAGE linked endothelial dysfunction may limit skeletal muscle blood flow and contribute to cardiovascular disease in the elderly.Support or Funding InformationNIH Heart, Lung, Blood Institute grants (HL‐ 091830) and Veterans Affairs Rehabilitation Research and Development Merit (E6910‐R)
Contribution of Adiponectin to Vascular Responses in Bone Resistance Arteries in Mice
Authors: Ghosh Payal , Hotta Kazuki , Lucero Tiffany , Borodunovich Kyle , Cowan Morgan , Bramy Jeremy , Behnke Bradley , Delp Michael , Delp Judy 
Published: November 2023

Adiponectin has been reported to alter structural properties of bone, which may be influenced by altered regulation of bone blood flow and related vasomotor properties in the bone resistance vasculature. Therefore, the purpose of this study was to determine the effects of adiponectin deletion on bone resistance arterial function.Adult male C57BL/6 wild‐type (WT) and homozygous adiponectin knockout (AdipoKO) mice were obtained for study. Femoral principle nutrient arteries (PNA) were isolated, cannulated and pressurized for in vitro study. Endothelium‐dependent (ACh, 10−9–10−4 M) and ‐independent (Dea‐NONOate, 10−9–10−4 M) vasodilation, and myogenic (0 to 130 cmH2O) responsiveness were evaluated.Endothelium‐dependent vasodilation was significantly impaired in PNA arteries from AdipoKO mice compared to arteries from WT mice; however, no significant differences in endothelium‐independent vasodilation were observed between arteries from WT and AdipoKO mice. Myogenic responsiveness tended to be greater in arteries from AdipoKO mice than arteries from WT mice. The greater myogenic tone seen in PNA arteries from AdipoKO mice may be linked to endothelial dysfunction.These results indicate that in bone resistance arteries, adiponectin modulates endothelium‐dependent vasodilation but does not affect vasodilatory function of the vascular smooth muscle. These alterations in vasomotor function could potentially play a role in alterations of bone structural properties associated with changes in circulating adiponectin.
Pharmacological or Genetic Interruption of Focal Adhesion Kinase Improves Endothelial Barrier Dysfunction Resulting from Ischemia/Reperfusion Injury
Authors: Haines Ricci J , Zhang Shimin , Eitnier Rebecca A , Wang Fang , Yang Clement GY , Wu Mack H 
Published: November 2023

Ischemia reperfusion (I/R) injury results from reoxygenation following an initial ischemic insult. Although oxygen levels are restored during reperfusion, the abrupt increase in blood supply results in high levels of reactive oxygen species that leads to endothelial barrier dysfunction and exacerbates the tissue injury originally elicited by the ischemic event. One therapeutic strategy used to enhance the endothelial barrier and prevent further tissue damage is to treat the exacerbated tissue damage caused by reperfusion. Our lab and others have shown that focal adhesion kinase (FAK) is a key player that participates in the signaling events required for endothelial barrier dysfunction. Therefore, we hypothesized that targeting FAK pharmacologically would improve I/R injury in vitro and in vivo. Using murine intestinal endothelial cells, we performed electric cell‐substrate impedance sensing (ECIS) assays with and without FAK inhibitor (PF573228, 1μM) in the presence of H2O2 (250μM). Results showed that FAK inhibition significantly attenuated barrier dysfunction induced by H2O2. Similarly, we also utilized FITC‐albumin flux assays to determine whether targeting FAK improved barrier function resulting from H2O2. These experiments showed that the increase of endothelial albumin flux due to treatment with H2O2 was reduced by approximately 50% when cells were pretreated with FAK inhibitor. Western blots of endothelial cell lysates treated with H2O2 indicated that FAK is activated in as little as 10 minutes and remains elevated for 60 minutes of treatment. Other experiments showed that the use of PF573228 dramatically reduced detection of active FAK (pY397 FAK) as well as total tyrosine phosphorylated proteins despite the presence of inflammatory signals. Using an in vivo model of I/R injury and endothelial specific, tamoxifen inducible, FAK knockout transgenic animals, as well as wild type animals given PF573228, we showed that interruption of FAK activity or expression reduced albumin leakage induced by I/R injury by over two‐fold, while neither mean arterial blood pressure nor diameter was altered by the drug or genetic manipulation. Taken together, these results suggest that targeting FAK may be a novel strategy to improve endothelial barrier dysfunction that occurs as a consequence of I/R injury.Support or Funding InformationNIH HL‐120954
The Role of Formyl Peptide Receptors (FPRs) in Cerebral Microvascular Dysfunction in Sickle Cell Disease
Authors: Gavins Felicity N. E. , Ansari Junaid , Senchenkova Elena Y. , Vital Shantel A. 
Published: November 2023

Cerebrovascular disease is a leading cause of death worldwide. It is a serious complication of sickle cell disease (SCD), an inherited autosomal recessive disorder, resulting from a single amino acid substitution in the haemoglobin β chain. Patients with SCD are more susceptible to thrombotic events, in which leukocytes, platelets and erythrocyte adhesion have all been implicated. It is therefore not surprising that SCD is frequently referred to as a “hypercoagulable state” characterized by a proinflammatory and prothrombogenic phenotype.The causes for the prothrombotic SCD phenotype may relate to a well‐established link between thrombosis and inflammation: Systemic inflammation can beget local thrombosis, and thrombosis can amplify inflammation. Accumulating data linking inflammation and thrombosis supports the hypothesis that anti‐inflammatory mediators may limit thrombosis and that anti‐thrombotic mediators may reduce vascular inflammation. One such anti‐inflammatory endogenous mediator is the glucocorticoid‐regulated protein Annexin A1 (AnxA1), which has been shown to dampen inflammation by e.g. the inhibition of leukocyte recruitment and cytokine release, promotion of apoptosis, stimulation of phagocytosis, and decreasing vascular permeability. The biological effects of AnxA1 occur through an interaction with the formyl peptide receptors (FPRs). In humans three FPRs (FPR1, FPR2, and FPR3) regulate innate inflammatory responses. Their function has been most extensively investigated in the context of leukocyte recruitment and activation, where FPRs promote cell motility (chemotaxis) and microbicidal respiratory burst.Here we have tested the effect of targeting the AnxA1‐FPR pathway as a therapeutic strategy for SCD. Data presented during the talk adds to the current literature suggesting a pro‐inflammatory and pro‐thrombogenic cerebral microcirculation is found in SCD mice. Furthermore, SCD appears to promote the formation of thrombosis, which can be inhibited by the administration of AnxA1 via the FPR pathway.Support or Funding InformationThe NIH/NHLBI (HL125572‐01A1)