bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin‐Mediated Vasodilation in Cerebral Arteries is Impaired in Obese Rats with Type 2 Diabetes
Authors: Olver T. Dylan , McDonald Matt W , Klakotskaia Diana , Richardson Rachel A , Jasperse Jeffrey A , Yang Hsiao T , Thorne Pam K , Melling C.W. James , Schactman Todd R. , Emter Craig A , Laughlin M. Harold 
Published: November 2023

Insulin stimulates resistance artery vasodilation in skeletal muscle and the brain. Type 2 diabetes (T2D) attenuates insulin‐induced vasodilation in skeletal muscle arteries, but whether this adaptation occurs in the cerebrovasculature and is related to impaired cognition remains to be elucidated. This study tested the hypothesis that cognition and insulin‐mediated vasodilation in the cerebrovasculature were impaired in obese rats with type 2 diabetes. Eight week old hyperphagic, Otsuka Long Evans Tokushima Fatty rats were divided into two groups; food controlled (CON, n=8) and free food access (model of T2D, n=8). Cognition was measured monthly using a Barnes maze for 4 months (i.e. at 8, 12, 16 and 20 wk of age) prior to vascular testing. At 20 wk of age, rats underwent a euglycemic hyperinsulinemic clamp, while carotid artery blood flow (BF; perivascular flow probe) and mean arterial pressure (MAP; arterial catheter) were measured. Thereafter, rats were decapitated, their cerebral arteries were isolated, and vasomotor responses (pressurized myography) to graded increases in intraluminal pressure (40–140 mmHg) and exogenous insulin (1–10000 uIU) were assessed in untreated and endothelin‐1 inhibition (BQ123) conditions. Results indicate that cognition improved over time, but was not different between groups at any time point. Carotid BF, MAP and vascular conductance (BF/MAP) were also not different between groups and did not change during the insulin clamp. Prior to and following the development of spontaneous tone, absolute diameter of the cerebral arteries was not different between groups. Vasomotor tone increased similarly in both groups during graded increases in intraluminal pressure (40–140 mmHg; P<0.05). Insulin‐mediated vasodilation (at 80 mmHg pressure) was attenuated in the T2D vs. CON (peak dilation = ~10 % vs. 30%; P<0.05). Endothelin‐1 inhibition restored insulin‐mediated vasodilation in the T2D group. A priori pairwise comparison between the cumulative average percent possible insulin‐mediated vasodilation in the untreated vs. endothelin‐1 inhibition conditions revealed that endothelin‐1 significantly restrained insulin‐mediated vasodilation in the T2D, but not the CON group (P<0.05). Thus, at this stage in development of T2D (~20 wk is the onset in this model), cognition, and cranial flow at rest and during an insulin clamp appear unaffected; even though isolated cerebral arteries exhibit vascular insulin resistance. These data from isolated cerebral arteries support the notion that impaired insulin‐mediated cerebral vasodilation in T2D is the result of enhanced insulin‐stimulated endothelin‐1 production.Support or Funding InformationCollege of Veterinary Medicine, University of Missouri‐Columbia
The Effects of Captopril Treatment and Exercise and Blood Pressure, Endothelium Function and Gene Expression of the Renin Angiotensin System in the Spontaneously Hypertensive Rat
Authors: Enyinnia Diamond Enyinnia , Henry Eden , Okoire Nnaemeka , Vaden Deirdre , Keaton Alphonso 
Published: November 2023

Angiotensin converting enzyme inhibitors (ACE‐I) have been show to prevent impairment of endothelial cell function in the Spontaneously Hypertensive Rat (SHR). The purpose of this study was to examine the combined effects of long‐term exercise training and ACE‐I treatment on blood pressure, vascular reactivity and gene expression of the Renin Angiotensin System (RAS), in the SHR. Three groups of male SHR were studied: 1) untreated SHR; 2) exercise trained (35 cm/s) for 60 minutes/day, for 3 days/week (SHREX); 3) exercised trained + captopril treated (50 mg/kg/day), treatment was initiated at four weeks of age and continued for 16 weeks (CAPEX). N = 8, for all three groups. At 20 weeks of age, systolic blood pressure (via tail cuff) in the untreated SHR was 190±11 mmHg. Exercise treatment in the SHR significantly decrease MAP in the SHREX was 151±7 mmHg). The combination of exercise and oral administration of captopril was associated with a significant decrease in systolic blood pressure (130±3 mmHg) compared to untreated SHR and SHREX. Isolated 3mm aortic ring segments were suspended in tissue chambers for measurement of isometric force. Ring segments were exposed to cumulative concentrations of serotonin (3× 10−9 – 3 × 10−5M). Preliminary data from aortic rings from SHR demonstrated increased responsiveness to serotonin induced contraction in comparison to aortic rings from the SHREX and CAPEX group. Endothelium‐dependent relaxation to acetylcholine was dramatically impaired in the SHR. Harvested tissue samples from the brain, kidney liver and blood will be used to examine gene expression of the renin angiotensin system using Next Generation RNA Sequencing.Support or Funding InformationMini Grant Award from the Office of Research and Graduate School, Prairie View A&M University
The Effect of Salbutamol on the Vasculature Differs in Asthmatics As Compared to Healthy Controls
Authors: Moore Linn E , Byers Bradley W , Kapoor Karishma , Stickland Michael K 
Published: November 2023

INTRODUCTIONAsthmatics are at increased risk of cardiovascular (CV) disease and inhaled beta(β)2‐agonist use is associated with increased CV events. Short‐acting β2‐agonists acutely affect cardiovascular function among healthy individuals. However, chronic β‐agonist use, often seen in asthma, is associated with β2‐refractoriness within the airways. It is unknown if the vascular responses to a clinically relevant dose of acute β2‐agonist differ between asthmatics and healthy controls.PURPOSETo compare the vascular response to an inhaled β2‐agonist between controls and asthmatics.METHODSEight asthmatics and 8 healthy controls matched for age, height and weight were recruited for the study. Average short‐term β2‐agonist usage among the asthmatics was 3.1 times/week for 11.5 years. Blood pressure (BP; mmHg), arterial stiffness (PWV; m/s), microvascular function (VTI; cm/s), and endothelial function (FMD; % baseline/shear rate) were examined before and after inhaled beta agonist (4 x 100 μg Salbutamol), or placebo. The order of test days was randomized, but all testing was conducted at the same time of day following a 12 hour fast. Respiratory medications were withheld for 8 hours prior to each test day.RESULTSThere were no baseline differences in arterial stiffness between groups. However, arterial stiffness increased in asthmatics but not controls acutely following Salbutamol administration (ΔPWV: +0.62 vs. −0.08 m/s, p<0.05). There was no between‐group difference in endothelial function or microvascular function at baseline; nor following β2‐agonist inhalation. Both groups had increased systolic blood pressure following Salbutamol administration which was not seen with placebo (Placebo: 109 to 108 mmHg, Salbutamol: 108 to 113 mmHg, p<0.05).CONCLUSIONAsthmatics have an altered acute vascular response to a clinically relevant dose of a short‐acting β2‐agonist, which results in an increase in arterial stiffness in asthmatics which is not seen in controls. The vascular stiffening in response to beta‐agonist use may contribute to the elevated CV risk seen in asthma.Support or Funding InformationThe Lung Association, Alberta & NWT
Vitamin D Receptor Expression is Essential for the Antiangiogenic Activity of Vitamin D
Authors: Jamali Nasim , Sorenson Christine M , Sheibani Nader 
Published: November 2023

Vitamin D compounds inhibit the growth of a variety of tumors perhaps through inhibition of angiogenesis. We previously showed that the active form of vitamin D, calcitriol (1, 25‐dihydroxyvitamin D3), is a potent inhibitor of neovascularization. However, the molecular and cellular mechanisms involved remain unknown. Here we determined whether the expression of the vitamin D receptor is essential for the antiangiogenic activity of vitamin D using mice deficient in vitamin D receptor (Vdr −/−). We also determined the impact of VDR deficiency in postnatal development of retinal vasculature. Wild type (Vdr +/+), heterozygous (Vdr +/−), and null (Vdr −/−) mice were subjected to oxygen‐induced ischemic retinopathy (OIR). During OIR postnatal day 7 (P7) mice are exposed to 75% oxygen for 5 days (P12) and then brought to room air for 5 days (P17). Maximum neovascularization occurs from P12‐P17 and degree of neovascularization is assessed at P17. To determine antiangiogenic activity of vitamin D animals received a daily intraperitoneal injection of calcitriol from P12‐P17. We showed that VDR expression is essential for inhibition of neovascularization, which was most evident in the female mice. Calcitriol failed to inhibit neovascularization in Vdr −/− mice compare to Vdr +/+ or Vdr +/− mice. Furthermore Vdr −/−, unlike the Vdr +/+, continued to gain weight following calcitriol treatment. We also observed a significant effect on the density of retinal vasculature and the number and structure of major retinal arteries during normal development. Mechanistically, we showed that retinal pericytes (PC) express significantly higher level of VDR compared with retinal endothelial cells. Calcitriol also attenuated the proliferation and migration of PC, and caused G0/G1 arrest without affecting apoptosis. Together, our results demonstrate an important role for VDR expression and inhibition of neovascularization perhaps through attenuation of PC proliferation and migration.Support or Funding InformationP30 EY016665, RPB, and RRF.
Preeclampsia in the rat: validation of the deoxycorticosterone (DOCA)‐salt model
Authors: Hanson Andrea E , Stallone John N 
Published: November 2023

Preeclampsia (PE) is a multi‐system disorder that typically occurs during the second and third trimesters of pregnancy. PE complicates 7–10% of all pregnancies worldwide and is a major cause of fetal and maternal morbidity and mortality. The hallmarks of PE include pregnancy induced‐hypertension (PIH), proteinuria, reduction in renal function, intrauterine growth restriction (IUGR) of the fetus, chronic immune activation, and multi‐organ dysfunction. The pathology of PE is not well understood. In the present study, DOCA‐salt treatment was validated as a model of PE in the female (F) Sprague‐Dawley rat. Normal pregnant (NP) and DOCA‐salt treated pregnant (DSP) F rats were studied, using time release DOCA‐impregnated silicone rubber implants (200 mg/kg) and saline drinking water (1% NaCl/0.2% KCl) from the onset of pregnancy until term. At term (day 18–20 of pregnancy), systolic blood pressure (tail cuff method) was elevated in DSP (146 ± 2 mmHg) vs. NP (115 ± 1 mmHg). In DSP, total urinary protein excretion was measurably higher in DSP (29.67 ± 11 mg/day) compared to NP (14.25 ± 10 mg/day). In addition, fetal weight was lower in DSP (2.52 ± 0.09 g) than in NP (4.05 ± 0.34 g), and maternal body weight was higher in NP (388 ± 5 g) compared to DSP (355 ± 25 g). These data suggest that DOCA‐salt treatment creates an accurate model of PIH and PE in the F rat.Support or Funding Information(State of Texas)
Angiotensin II Type 1 Receptor Agonistic Autoantibody Inhibition Improves Maternal Outcomes in Reduce Uterine Perfusion Pressure Rats
Authors: Cunningham Mark W. , Castillo Javier , Spradley Frank , Faulkner Jessica , Ibrahim Tarek , Elfarra Jamil , LaMarca Babbette 
Published: November 2023

BackgroundWomen with preeclampsia have hypertension, placental ischemia, intrauterine growth restriction, reduced glomerular filtration rate (GFR), elevated sFlt, preproendothelin (PPE), and agonistic autoantibodies to the Angiotensin II type 1 receptor (AT1‐AA) during pregnancy. The reduce uterine perfusion pressure (RUPP) rat model of placental ischemia during pregnancy, also displays elevated AT1‐AAs, blood pressure, sFlt, PPE, and a reduced GFR along with fetus and placenta demise. Due to the robust elevation of AT1‐ AAs in the pathophysiology of preeclampsia, we hypothesis that administration of a specific 7 amino acid peptide sequence (7AA) to inhibit the AT1‐AA, will improve blood pressure, sFlt, preproendothelin, GFR, and pregnancy outcomes in RUPP rats.MethodsDay 14 of gestation rats receive the RUPP procedure with or without the AT1‐AA inhibitory peptide (2ug/ml saline) via mini‐osmotic pumps, infusing 7AA peptide for 6 days. On day 19 of gestation, conscious blood pressure (MAP) and GFR were determined, pups and placentas were counted and weighed, and other tissues were collected. All rats were age matched to control normal pregnant (NP) rats.ResultsMAP was elevated in RUPP rats (n=28) vs. NP rats (n=10) (121±1 mmHg vs .98±3 mmHg, p<0.05; respectively). The rise in blood pressure was returned to NP baseline blood pressures in RUPP rats treated with the 7AA (n= 15; 104±3 mmHg, p<0.05). Pup weight, number of pups, and placental weight was decreased in RUPP rats vs. NP rats and remained unchanged with RUPP + 7AA rats. Circulating sFlt1 (176±37 vs. 77±15pg/ml, p<0.05) was elevated in RUPP rats vs. NP rats and was normalized in RUPP + 7AA rats (86±9 pg/ml, p<0.05). There was a 4 fold increase in PPE in RUPP (n=7) vs. NP (n=6) rats and a 2 fold decreased in PPE between RUPP + 7AA (n=7) vs. RUPP rats (p<0.05). GFR was improved in RUPP + 7AA (n=2) vs RUPP rats (n=3) (1.4±0.12 vs. 1.1±0.05 ml/min/100g BW).ConclusionAT1‐AA inhibition improves the maternal blood pressure, GFR, and secretion of anti‐angiogenic and vasoconstrictor factors in RUPP rats, and thus maybe a potential therapy for preeclamptic patients.Support or Funding InformationResearch Supported by T32HL105324 and RO1HD067541
Increased Myogenic Tone and Underlying [Ca2+]i and Arterial Stiffness in Mesenteric Microvessels of Hypertensive Pregnant Rats
Authors: Mazzuca Marc Q. , Buyukcelebi Kadir , Ren Zongli , Zhu Minglin , Khalil Raouf A. 
Published: November 2023

Preeclampsia is a pregnancy‐related hypertensive disorder (HTN‐Preg) with unclear mechanisms. We have previously shown enhanced vasoconstriction and microvascular reactivity to external KCI‐induced membrane depolarization and endothelin‐1 in HTN‐Preg rats with reduced uterine perfusion pressure (RUPP). However, whether HTN‐Preg involves changes in the intrinsic myogenic responses of systemic microvessels is less clear. In Norm‐Preg and RUPP rats on day 19 of pregnancy, BP was recorded and mesenteric microvessels were isolated and mounted on a pressure myograph system for measurement of myogenic tone, arterial stiffness and simultaneous changes in [Ca2+]i (fura‐2 340/380 ratio). Microvessels were incubated in Ca2+ containing Krebs or 0 Ca2++EGTA Krebs and pressurized from 0–110 mmHg in 10 mmHg increments for measurement of active or passive myogenic responses, respectively. The myogenic response was expressed as % change in vessel diameter from initial diameter at 10 mmHg. BP was higher in RUPP (133±3 mmHg) than Norm‐Preg rats (102±2 mmHg). In Ca2+ containing Krebs, active myogenic tone was greater in microvessels of RUPP (34.5±2.6%) than Norm‐Preg rats (26.5±2.9%), and was associated with greater increases in [Ca2+]i in RUPP (0.90±0.01) than Norm‐Preg rats (0.86±0.01). In 0 Ca2++EGTA Krebs, the passive myogenic response was also increased in microvessels of RUPP (36.2±1.1%) vs. Norm‐Preg rats (19.3±1.2%), with no underlying changes in [Ca2+]i, suggesting changes in the structure and mechanics of the arterial wall. The active and passive stress‐strain relationship for microvessels of RUPP rats was shifted to the left compared to Norm‐Preg rats, suggesting increases in arterial wall stiffness. Thus, the increase in BP in placental ischemia model of HTN‐Preg is associated with increased myogenic tone and arterial stiffness in mesenteric microvessels. These results suggest that intrinsic alterations in vascular smooth muscle Ca2+ signaling as well as structural changes in the microvascular wall architecture could play a role in the increased vasoconstriction and BP in HTN‐Preg.Support or Funding InformationThis work was supported by grants from the National Heart, Lung, and Blood Institute (HL‐65998, HL‐111775). M.Q. Mazzuca is a recipient of American Heart Association Postdoctoral Fellowship (Founders Affiliate) Award no. 14POST18150007.
Inhibition of hypoxia inducible factor‐1α in the renal medulla contributes to fructose‐induced salt‐sensitive hypertension
Authors: Hu Junping , Zhu Qing , Li Pin‐Lan , Boini Krishna M. , Li Ningjun 
Published: November 2023

Excessive fructose ingestion has been closely associated with hypertension and shown to increase the salt sensitivity of blood pressure. We have previously demonstrated that high salt‐induced activation of hypoxia inducible factor (HIF)‐1α in the renal medulla is an important adaptive mechanism to remove extra sodium load and maintain normal blood pressure in response to a high salt intake. The present study tested the hypothesis that dietary fructose inhibits high salt‐induced activation of HIF‐1α in the renal medulla and thereby increases salt‐sensitivity of blood pressure. Adult Sprague‐Dawley rats were divided into 4 groups: low salt diet (LS, 0.4%NaCl), high salt diet (HS, 8% NaCl), LS+fructose (20% in drinking water) and HS+fructose. After 10 day treatment, mean arterial pressure (MAP) was significantly higher in rats fed with HS+fructose than all other groups, whereas MAP was not different among groups of LS, HS and LS+fructose (MAP: 103 ± 4.7 mmHg in LS group, 104 ± 2.4 in LS+fructose, 105 ± 3.4 in HS, and 120 ± 2.03 in HS+fructose, P<0.05). Interestingly, high salt‐induced increase of renal medullary HIF‐1α protein levels was significantly inhibited by fructose. The relative levels of HIF‐1α in the renal medulla in groups of LS, HS, LS+Fructose and HS+Fructose were 1 ± 0.10, 2.05 ± 0.36, 0.18 ± 0.008, 0.19 ± 0.05 (P<0.05), respectively. The mRNA levels of HIF‐1α target gene heme oxygenase (HO)‐1 was also inhibited by 69% in HS+Fructose group compared with HS group. Furthermore, overexpression HIF‐1α transgene in the renal medulla corrected the reduced levels of HIF‐1α and its target gene HO‐1 in the renal medulla and attenuated the increase of blood pressure induced by HS+fructose (MAP: 104 ± 3.9 mmHg in LS group, 107 ± 2.3 in LS+fructose, 107 ± 3.1 in HS, 124 ± 3.4 in HS+fructose, and 114 ± 1.4 in HS+fructose+HIF‐1α transgene, P<0.05). These results suggested that inhibition of HIF‐1α‐mediated gene activation in the renal medulla participates in the mechanisms of fructose‐induced salt‐dependent hypertension, and manipulating HIF‐1α signaling pathway may be used as a therapeutic strategy in fructose‐induced salt‐dependent hypertension.Support or Funding Informationsupport: NIH grant: HL89563 and HL106042
Sources for anti‐inflammatory annexin A1 signals during acute anti‐Thy‐1.1 nephritis
Authors: Labes Robert , Dittert Philipp , Bachmann Sebastian , Paliege Alexander 
Published: November 2023

Leukocyte infiltration presents a hallmark feature of immune‐mediated acute kidney injury and defective resolution of inflammation may promote progression towards chronic kidney failure. Leukocytes exert distinctive effects during this process and may either aggravate kidney damage or foster renal repair. The glucocorticoid‐inducible protein Annexin A1 has been shown to induce resolution of inflammation and to shift macrophage polarization towards the anti‐inflammatory and repair‐promoting M2 phenotype. The cellular source of the putative Annexin A1 signal and its regulation during the course of renal inflammation remains to be elucidated.Adult Wistar rats were injected with an antibody directed against the Thy‐1.1 protein located on mesangial cells to induce mesangioproliferative glomerulonephritis. Animals were examined after 24h (initiation phase), 5d (proliferation phase), and 15d (resolution phase). Regulation of Annexin A1 was studied by qPCR and immunohistochemistry. Annexin A1+ cells were characterized by triple labelling immunofluorescence using antibodies for CD68 (monocytes and macrophages), CD206 (macrophages with M2 polarization), CD3, CD4, and CD8 (T‐cell subpopulations), CD20 (B‐lymphocytes), and myeloperoxidase (neutrophil granulocytes). Quantification of immunoreactive cells was performed by cell counting on confocal micrographs.Renal Annexin A1 mRNA levels increased rapidly after induction of anti‐Thy‐1.1 nephritis (24h: +92±16%; 5d: +128±19%; 15d: +78±33% relative to controls; p<.05). Immunofluorescence labelling showed an interstitial accumulation of total, and CD206+ M2 macrophages during the proliferation and resolution phase (5d: +150±40% and +260±29%; 15d: +378±43% and +600±100% relative to controls; p<.05). Elevated numbers of CD68+/CD206+/Annexin A1+ interstitial M2 macrophages were revealed by triple labelling studies at d5 and d15 (+240±27% and +450±80% relative to controls; p<.05). Abundant expression of Annexin A1 was further found in CD4+ and CD8+ T‐lymphocytes but their number remained unaffected by renal inflammation. CD20+ B‐lymphocytes were negative for Annexin A1. Granulocytes were found in subset of glomeruli at 24h and d5. All granulocytes stained positive for Annexin A1.In conclusion, we have shown a significant increase of Annexin A1 gene expression and protein abundance during the course of anti‐Thy‐1.1 nephritis. The increased amount of Annexin A1+ leukocytes in animals with anti‐Thy‐1.1 nephritis suggest that these cells present a major source for anti‐inflammatory and pro‐resolving signals during renal inflammation.Support or Funding InformationDeutsche Forschungsgemeinschaft; FOR1368
Uncoupling Protein‐2 Deficiency Protects Kidney Function in Ageing Mice
Authors: Carvalho Carla , Schiffer Tomas , Hansell Peter , Palm Fredrik 
Published: November 2023

Increased kidney oxygen consumption due to increased mitochondrial leak respiration contributes to chronic kidney disease. Physiological leak respiration in the kidney is mainly mediated by uncoupling protein‐2 (UCP‐2) since it is the only UCP expressed in this tissue. However, it is not known how UCP‐2 affects long term kidney function in the ageing kidney although we hypothesize that UCP‐2 deficiency protects kidney function in aged mice.In this study, 2 year old wild‐type and UCP‐2 deficient mice (B6.129S.UCP2<tm1Low>lJ, Jackson Lab) were placed in metabolic cages for 24h urine collection followed by determination of conscious arterial blood pressure using the tail cuff method and glomerular filtration rate using a single bolus injection of FITC‐inulin.UCP‐2 deficient mice had similar water and food intake as well as body and kidney weights compared to wild‐type mice. However, systolic blood pressure was higher in UCP‐2 deficient mice (systolic 95±5 versus 88±3 mmHg) whereas diastolic pressure was similar in the two groups (62±4 versus 61±2 mmHg). Interestingly, urinary protein excretion was approximately 30% lower in UCP‐2 deficient mice and glomerular filtration rate significantly higher (307±30 versus 228±30 μl/min) compared to corresponding wild‐type animals.In conclusion, these results demonstrate that UCP‐2 deficiency protects long‐term kidney function in ageing mice by reducing urinary protein leakage and maintaining normal glomerular filtration rate. Thus, treatment options aiming to reduce the age‐related activation of UCP‐2 may improve kidney status in the ever growing population of older people.Support or Funding InformationSwedish Research Council and Swedish Diabetes Foundation