bluuebunny/crossref_metadata_2025_split huggingface dataset:
CARDIOVASCULAR EFFECTS INDUCED BY LINALOOL AFTER SUBCHRONIC TREATMENT OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Camargo Samuel Barbosa , Simões Letícia Oliveira , de Azevedo Medeiros Carla Fiama , de Melo Jesus Anderson , de Jesus Silva Jailton , Fregoneze Josmara Bartolomei , Silva Darizy Flavia 
Published: November 2023

IntroductionLinalool (LIN) is an alcoholic monoterpene with biological activities previously described. This study in order to evaluate the cardiovascular effects in vivo subchronic treatment of spontaneously hypertensive rats (SHR) is focusing on antihypertensive properties of linalool.MethodsAll experiments were performed with SHR aged 9–12 weeks and (−)‐linalool (≥ 97 % purity) was solubilized in cremophor in a ratio of 2:1 and diluted with physiological saline solution (100 mg/kg) and controls solutions captopril (30 mg/kg) and vehicle (saline + cremophor) were administered daily for 21 days by orogastric injections. Each 5 days the arterial pressure and the heart rate were measured by tail cuff method. At the end of treatment, mesenteric artery was isolated to reactivity tests and the heart was removed and placed in an oven to dry at 60° C, for 24 to 48 hours, to obtain the dry weight.ResultsAnimals treated with linalool, vehicle and captopril showed no statistically significant differences at the levels of water consumption and feeding and no difference in progressive increasing body weight between the three groups. None of the treated groups had significant changes in the values of heart rate. Animals treated with vehicle showed a progressive increase in the mean arterial pressure (MAP). Captopril induced a significant decrease at MAP, from the fifth day of treatment and (−)‐linalool was able to maintain the initial pressure values, avoiding the progression of hypertension and demonstrating a significant reduction in the blood pressure at fifteenth day. The subchronic treatment with linalool decreases the cardiac mass index similar to that found in animals treated with captopril when compared to the negative control group. Finally, linalool induced beneficial changes in vascular responsiveness.ConclusionThese results suggest that linalool, after 21 days of subchronic treatment of spontaneously hypertensive rats, demonstrated antihypertensive potential inducing the maintenance and decrease of the mean arterial pressure with no changes in heart rate, being able to reduce cardiac hypertrophy, to decrease vascular reactivity to a vasoconstrictor agent phenylephrine (PHE) and to increase pharmacological potency to a vasodilator agent sodium nitropusside (SNP).3012 ‐ ASPET Cardiovascular Pharmacology – General/OtherSupport or Funding InformationFundação de Amparo à Pesquisa do Estado da Bahia (FAPESB) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Lipocalin‐2 Deficiency Protects against Aldosterone‐Induced Hypertension and Organ Damages by Inhibiting Mineralocorticoid Receptor Signaling
Authors: Yang Kangmin , Luo Cuiting , Cheung Bernard MY. , Félétou Michel , Vilaine Jean‐Paul , Villeneuve Nicole , Xu Aimin , Vanhoutte Paul M. , Wang Yu 
Published: November 2023

Lipocalin‐2, an adipokine dysregulated in cardiometabolic syndrome, is causatively involved in the development of obesity‐related endothelial dysfunction and hypertension. The present study investigated the contribution of lipocalin‐2 to aldosterone‐induced pathologies involving mineralocorticoid receptors (MR). Mice were treated during four weeks with vehicle, angiotensin II or challenged with the combination of aldosterone plus uninephrectomy and administration of 1% saline in the drinking water (ANS). In mice without lipocalin‐2 (LKO), the gene expression levels of MR in heart, kidney, adipose tissue and aorta are significantly lower than those of wild‐type (WT) controls. ANS significantly increased arterial blood pressures in WT but not LKO mice. Moreover, lipocalin‐2 deficiency prevented ANS‐induced fibrotic damages in heart and kidneys. Treatment with the MR antagonist, spironolactone, protected mice against ANS‐induced hypertension and organ damages to a similar extent as lipocalin‐2‐deficiency. On the other hand, angiotensin II‐induced elevation of blood pressure was not affected significantly by either lipocalin‐2‐deficiency or MR inhibition. The mechanistic involvement of lipocalin‐2 in aldosterone‐stimulated MR expression and/or activation was further investigated. Collectively, the results demonstrate that lipocalin‐2 plays a critical role in the cardiovascular damage induced by activation of the aldosterone‐MR signaling axis.Support or Funding InformationThis work was supported by the grants from Hong Kong Research Grant Council [General Research (17121714, HKU 763312 and HKU 780613M), Collaborative Research Fund (C7055‐14G)] and an educational grant from Les Laboratories Servier (RS100503).
PRR activates canonical Wnt signaling pathway during pregnancy‐induced hypertension in rats
Authors: Lopez Pedro , Ramirez‐Montero Claudia , Anguiano‐Robledo Liliana , Avila‐Ramirez Massiel A. , Hernandez‐Campos Maria Elena 
Published: November 2023

Pregnancy is a physiological condition with profound hemodynamic changes. Pregnancy‐induced hypertension (PIH) is a common and severe complication. There is no a clear cause, but several systems have been involved. Renin Angiotensin Aldosterone System (RAAS) is one of them. Prorrenin renin receptor (PRR) a component of this system could play a role in PIH physiopathology. This receptor has been associated to Wnt signaling pathway, both canonical and non‐canonical. In this work we studied the posible activation of Wnt pathway by PRR in a PIH model in rats. We submitted female Wistar rats to sub‐renal aortic coarctation (SRAC) to induce PIH, set in control, pregnant‐non SRAC and pregnant‐SRAC groups. We measured blood pressure, proteinuria and offspring weight and size. We determined b‐catenin, DVL‐1, HDA4, JNK‐1and PKCa in aorta, heart, and kidney by immunoblot. We found and increased expression of PRR, b‐catenin, HDA4 and DVL‐1 in cardiac, renal and aortic tissue from PIH animals. Similar findings were shown using immunohistochemistry on same tissues. No significant changes were found in JNK‐1 and PKCa in any tissue. These results suggest that canonical Wnt pathway seems to be activated in the studied tissues during PIH, whereas non‐canonical pathway seems not to have a role in it.Support or Funding InformationSupported by SIP20150457 grant
Motivating Young Investigators to Pursue Cancer Research Careers and Training
Authors: Kidd LaCreis Renee , Hein David W. 
Published: November 2023

University of Louisville Cancer Education Program (CEP), funded by a National Cancer Institute (NCI) grant, seeks to educate, and motivate undergraduate and professional students to pursue further training and future careers in cancer research. Over the past 4 years, 121 participants completed the program, including 42% females, 16% African‐Americans, 12% Asians, 2.4% Hispanic/Latino, 2.4% Indian, and 2.4% mixed. All trainees formulated a cancer research project in collaboration with their faculty mentor engaged in cancer research at the Brown Cancer Center. Laboratory research training/mentoring was supplemented with cancer‐related seminars and professional development activities. A blinded survey was used to assess participants’ perspective on program components. Participants ranked the programmatic activities as “poor”, “could be better”, “neutral”, “good”, and “excellent”. Over the past four years, there was a significant improvement in the participants’ interest in cancer research after completing the program (P < 0.0001). The interest level in cancer research improved, remained the same, or decreased among 46.5%, 45.4%, and 8.2%, respectively. A majority of the students perceived the overall program experience (86.4%), quality of the faculty mentor (88.5%), helpfulness of lab mentor (86.3%), and quality of the professional development activities (84.4%) as “good to excellent”. R25 alumni have presented their research at national/international scientific meetings (n = 22), published their research in scholarly journals, and continue their cancer research/oncology training at various post‐graduate degree programs/institutions (n = 32). UofL's Cancer Education Program is well poised to produce the next generation of cancer researchers.Support or Funding InformationThe program is supported by NCI grant R25‐CA134283.
Outcomes of a Dedicated Pharmacy Student Summer Research Program
Authors: Brandl Katharina , Adler David , Kelly Carolyn , Taylor Palmer , Best Brookie 
Published: November 2023

ObjectivesThis study investigated the impact of an optional 12‐week Summer Research Program on the publication outcomes and satisfaction with the required research projects of Pharm.D. students at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego (SSPPS).MethodsPubMed and Google searches provided student publications, and satisfaction surveys submitted by students and preceptors provided their perceptions of the research project value.ResultsOf the studied cohort, the 130 students who fulfilled the requirement through the optional Summer Research Program provided 61 full‐text manuscripts and 113 abstracts. The 305 students who chose the standard pathway provided 35 full‐text manuscripts and 34 abstracts. Students and preceptors in both pathways agreed or strongly agreed that the research project was a valuable experience.ConclusionsThe 12‐week intensive Summer Research Program improved the publication rate of pharmacy students and provided a high overall satisfaction with this independent learning experience.
Distinct EC coupling mechanism drives spatial control of vascular tone in cerebral arteries
Authors: Zechariah Anil , Hald Bjorn Olav , Mazumdar Neil G. , Welsh Donald G. 
Published: November 2023

Cerebral arterial networks consist of thousands of segments that work together and in isolation, tuning the magnitude and distribution of brain blood flow. The existence of spatially distinct responses suggests that distinct excitation‐contraction (EC) coupling mechanisms are encoded into each arterial segment. This study sought to define which EC coupling mechanisms enable cerebral arterial segments to work together and in isolation, from one another. Using both theoretical and experimental approaches, we show that multi‐segmental responses require the sharing of charge via gap junctions. This process of “electrical communication” enables arteries to equilibrate membrane potential, synchronize Ca2+ concentration and coordinate myosin light chain phosphorylation among large populations of smooth muscle cells. In contrast, isolated vessel behavior was independent of charge sharing and electromechanical coupling. It depended upon: 1) the voltage‐independent generation of Ca2+ waves; and 2) direct catalytic subunit inhibition of myosin light chain phosphatase. The latter was found to be driven by protein kinase C and the phosphorylation of CPI‐17. Subsequent work revealed that the presence of distinct EC coupling mechanisms enabled multi‐segmental and isolated responses to simultaneously but independently co‐exist in a single artery. As such, the magnitude and distribution of brain blood flow can be concurrently tuned depending on the nature of the originating stimulus. Translationally, these findings indicate that the ‘one‐size‐fits‐all” strategy to treating blood flow abnormalities should be reconsidered and tailored to the underlying dysfunction in EC coupling.Support or Funding InformationThis work is supported by an operating grant to Dr Welsh from the Natural Science and Engineering Council of Canada (NSERC). Dr Welsh is the Roraback Chair in Neuroscience and Vascular Biology at the University of Western Ontario. A. Zechariah is supported by Canadian Institutes of Health Research (CIHR) Postdoctoral scholarship, Alberta Innovates Postdoctoral scholarship and Eyes High Postdoctoral fellowship.
Disruption In PKC‐mediated K Channel Regulation Contributes To Enhanced Serotonin Mediated Carotid Vessel Constriction from the Fawn Hooded Hypertensive Rat
Authors: Kaur Gurjit , Pabbidi Mallikarjuna 
Published: November 2023

Previous studies indicate Fawn Hooded Hypertensive (FHH) rats exhibit cerebral damage due to diminished cerebrovascular myogenic function associated with elevated BK channel function. Introgression of the 2.4 Mbp region of BN chromosome 1 into the FHH rat restored myogenic response and BK channel function in a FHH.1BN congenic rat. However, results obtained from resistance vessels cannot be extrapolated to conduit vessels due to structural and functional differences. Thus, the present study addresses the hypothesis that carotid vessels of FHH rats exhibit altered serotonin (5‐HT)‐mediated contraction compared to FHH.1BN rats. Using tension myography to measure conduit vascular function, we found that carotid vessels of FHH rats exhibited greater 5‐HT‐mediated contraction than FHH.1BN rats. Activation of BK channels (NS1619: 5 to 30μM) relaxed carotid vessels to a lesser extent (1.17 times less) in FHH rats. On the other hand, inhibition of BK channels (Paxilline or Iberiotoxin: 100nM) had no effect in either strain. Inhibition of voltage gated calcium channels (VGCC, Diltiazem: 10μM) or store operated calcium (SOC) channels (2‐APB: 75μM) relaxed carotid vessels similarly in both strains. Furthermore, PKC activation (PMA: 100nM) or inhibition (GF109203X: 3μM) increased and decreased 5‐HT‐mediated constriction respectively in FHH.1BN rats but had minimal effect in FHH rats. These results suggest that a mutation in the genes located in 2.4Mbp region in FHH rats contribute to a disruption in PKC and its regulation of K channels, causing enhanced 5‐HT‐mediated contraction.Support or Funding InformationThis research has received funding support from the American Heart Association, Scientist Development Grant (13SDG14000006) and the IOSP Undergraduate Summer Research Fellowship supported by the American Physiological Society and a grant from the National Science Foundation Integrative Organismal Systems Award No. IOS‐ 1238831.
Measurements of Blood Flow, Tissue Oxygen Tension, and Oxygen Consumption in Rat Skeletal Muscle during Recovery from Bouts of Brief, Transient Ischemia
Authors: Dodhy Sami C , Golub Aleksander S , Pittman Roland N 
Published: November 2023

In resting muscle, blood flow is regulated to meet the demand for O2 by the respiring tissue. A locally induced ischemia/reperfusion protocol was utilized to investigate the effects of transient ischemia (5, 15, 30, and 60 s duration) in rat skeletal muscle. The results will be utilized in a model that relates blood flow, interstitial oxygenation, and oxygen consumption. We anticipate that this study will aid in furthering our understanding of the local regulation of blood flow and tissue oxygenation. 29 spinotrapezius muscles from male Sprague‐Dawley rats were surgically exteriorized for intravital microscopy. Interstitial PO2 (PISFO2) and arteriolar PO2 (PaO2) measurements were made using phosphorescence quenching microscopy (PQM). Red cell velocity was measured using Optical Doppler velocimetry and used to calculate blood flow (Q). Oxygen consumption (VO2) was measured with a quasi‐continuous, flash‐synchronized, rapidly pressurizing airbag system to both initiate ischemia and sample the rate of change in oxygen tension (dPO2/dt). The average baseline value of arteriolar blood flow was measured as 5.8±0.8 μl/min; as expected, reactive hyperemia was observed during the recovery from ischemia. Flow recovery (dQ/dt) was fastest [3.88±0.64 (μl·min−1)/s] after 60 seconds of ischemia. Average baseline PISFO2 was 62±4 mmHg; PISFO2 decreased to 75%, 34%, 10% and 2% of baseline following 5, 15, 30 and 60 s of ischemia, respectively. Up to 30 s of ischemia, the rate of recovery of PISFO2 steadily increased as the ischemic duration increased; however, it dropped off following 60 seconds of ischemia. The rate of recovery of PISFO2 was fastest (4.2±0.7 mmHg/s) following 30 seconds of ischemia. Average baseline VO2 was 120±19 nl O2/cm3·s and it increased above baseline during the early part of the recovery period. As is consistent with our current understanding, the time course of recovery of PISFO2 represents a balance between oxygen delivery, proportional to the local arteriolar tissue perfusion, and local oxygen consumption. When the ischemic duration increased, the interstitial oxygen tension decreased. An assumption was made in the modeling process that the arteriolar oxygen tension did not change during the course of each trial. Further investigation of both intravascular and perivascular PaO2 using the PQM system and the same ischemia/reperfusion protocol will highlight any differences in the supply of oxygen to the interstitium versus what was already present at baseline.Support or Funding InformationSupported by AHA Award #14GRNT20380551
HS‐FGF2‐FGFR1 signaling contributes to pulmonary endothelial glycocalyx reconstitution
Authors: Schmidt Eric P , Yang Yimu , Suflita Matthew , Zhang Fuming , Dailey Kyrie , Haeger Sarah , Ford Joshay , Linhardt Robert 
Published: November 2023

The pulmonary endothelial glycocalyx (and its in vivo manifestation, the endothelial surface layer) is a heparan sulfate (HS)‐rich layer lining the vascular lumen. Degradation of ESL HS leads to collapse of ESL thickness, endothelial dysfunction and organ injury. Surprisingly little is known about the endothelial mechanisms underlying reparative HS synthesis and their contribution to ESL reconstitution. We treated C57BL/6 mice with heparinase‐III, a bacterial glucuronidase that specifically degrades ESL HS. Mouse lung intravital microscopy revealed that ESL reconstitution was nearly complete within 24 hours after heparinase‐III, coincident with pulmonary induction of the HS biosynthetic enzyme exostosin 1 (Ext1). ESL reconstitution was prevented by treatment with 4‐F‐GlcNAc, an inhibitor of Ext1 HS polymerization. Loss of ESL reconstitution was associated with the onset of lung edema. Similarly, Ext1 induction and ESL reconstitution did not occur mice with endothelial‐specific deletion of fibroblast growth factor receptors 1 (FGFR1); accordingly, these knockout mice demonstrated pulmonary edema. Using surface plasmon resonance and BAF3 cell arrays, we determined that HS fragments (released as a consequence of ESL degradation) may stimulate FGF2‐FGFR1 signaling, inducing Ext1 expression in a human pulmonary microvascular endothelial cell line. Our findings suggest that the products of ESL degradation (i.e. fragmented HS) initiate processes responsible for homeostatic pulmonary ESL reconstitution.Support or Funding InformationR01 HL125371
The Role of Matrix Metalloproteinases (MMPs) in Platelet Endothelial Cell Adhesion Molecule‐1 (PECAM‐1) Loss in Diabetic Retinopathy: In Vivo and in Vitro Studies
Authors: Eshaq Randa Shafiq , Harris Norman 
Published: November 2023

OBJECTIVEThe aim of this study is to understand the mechanisms involved in the diabetes‐induced loss of PECAM‐1 in the retina, and whether it can be attributed to PECAM‐1 cleavage by matrix metalloproteinases (MMPs).INTRODUCTIONPlatelet endothelial cell adhesion molecule‐1 (PECAM‐1) is expressed on the surface of endothelial cells of the vasculature, and has major roles in inflammation, permeability, and angiogenesis. In addition, PECAM‐1 functions in cell signaling, cell‐cell adhesion, and cell survival. However, its physiological role in the pathophysiology of diabetic retinopathy (DR), the leading cause of blindness among working age adults worldwide, has not yet been investigated. We have previously found a significant decrease (50–90%) in retinal PECAM‐1 levels in a diabetic model of type I diabetes in rats.DESIGN AND METHODSFor our animal studies, we injected age‐matched male Wistar rats with either vehicle (control) or streptozotocin (STZ, diabetic), with the latter at 30 mg/kg/day for three consecutive days to elicit a model of type I diabetes. For our in vitro studies, primary rat retinal microvascular endothelial cells (RRMECs) were grown in either normal glucose (NG, 5mM) or high glucose (HG, 25 mM) media, and treated for 6 days with 0 or 10% plasma collected from control or diabetic rats 8 weeks post‐injection. PECAM‐1, and MMP levels or activity, were assessed using immunofluorescence staining, western blotting, or zymography.RESULTSFor RRMECs grown in NG conditions, treatment with 10% diabetic plasma resulted in significantly lower levels of PECAM‐1 than treatment with 10% control plasma (27%, p<0.05). PECAM‐1 loss was further exaggerated when cells were grown under HG conditions and treated with 10% diabetic plasma (74%, p<0.01). In contrast, control plasma added to RRMECs in NG conditions increased the expression of PECAM‐1 in a dose‐dependent manner. These findings indicate that normal plasma contributes to the expression of PECAM‐1, but some factor(s) in diabetic plasma has the reverse effect. MMPs, which are calcium‐dependent zinc‐containing endopeptidases, are known to cleave PECAM‐1. Plasma samples from diabetic rats revealed a significant increase in MMP‐2 levels (2‐fold, p<0.05), and a significant increase in MMP‐7 activity (p<0.01). Moreover, RRMECs showed a significant increase in MMP2 levels (12‐fold, p<0.01) when grown in HG media.CONCLUSIONThese results indicate a possible role for MMPs in the diabetes‐induced loss of PECAM‐1. Further studies will be conducted to investigate the potential benefits of protecting the retinal expression of PECAM‐1 by targeting the actions of MMPs.Support or Funding InformationNIH RO1 EY017599
Norepinephrine Induces Endothelial Albumin Uptake via ROS and Src‐Dependent Mechanisms
Authors: Chignalia Andreia Zago , Isbatan Ayman , Minshall Richard , Dull Randal 
Published: November 2023

Hypertensive pulmonary edema often occurs acutely and is typically associated with normal left ventricular performance. Factors other than simple Starling forces may contribute to the molecular mechanisms by which increased blood pressure leads to acute endothelial barrier failure and lung edema.MethodsTo mimic an adrenergically‐mediated hypertensive crisis, we administered norepinephrine (NE) to rats and assessed indices of edema development. Rats were anesthetized with isoflurane and mechanically‐ventilated; subjects received an infusion of NE to target a MAP = 150mmHg. Lung wet/dry ratio, ΔPaO2, plasma hematocrit, lung MPO activity, BAL protein and cell analysis were assessed. Inhibition of nitric oxide synthase (NOS) by L‐NAME was used to test the contribution of endothelial mechanotransduction on changes in permeability. In parallel studies, rat lung microvascular endothelial cells were stimulated with norepinephrine in the presence or absence of propranolol (10−5M, β‐adrenoceptor antagonist), phentolamine (10−5M, α‐adrenoceptor antagonist), PP2 (10−5M, Src inhibitor), apocynin (3×10−5M, ROS scavenger), or L‐NIO (10−4M, NOS inhibitor). Reactive oxygen species (ROS) production was determined by DHE fluorescence. Albumin uptake was assessed by ELISA and albumin transport was measured by fluorimetry.ResultsNE‐treated rats had a decrease in PaO2, an increase in lung albumin content, MPO activity and wet/dry ratio. BAL fluid had increased protein content and number of macrophages indicative of inflammation. L‐NAME significantly attenuated NE‐induced pulmonary edema. In vitro, albumin uptake and transport was increased by NE in a time‐dependent manner. ROS production was augmented by NE. Phentolamine, PP2 and apocynin decreased NE‐induced albumin uptake and ROS generation, effects not altered by L‐NIO.SummaryWe describe a novel pathway whereby norepinephrine stimulates albumin uptake and potentially endothelial permeability which might be important in hypertensive pulmonary edema.Support or Funding InformationDepartment of Anesthesiology, University of Illinois at Chicago