Obesity and diabetes are major risk factors for cardiovascular diseases. Zucker fatty diabetes mellitus (ZFDM) rats are novel animal model of obesity and type 2 diabetes. We have recently reported that blood pressure in ZFDM-Leprfa/fa (Homo) rats was normal, while blood adrenaline level and heart rate were lower than those in control ZFDM-Leprfa/+ (Hetero) rats. Here, we compared the reactivity in isolated mesenteric artery between Hetero and Homo rats. Contraction induced by phenylephrine was increased, while relaxation induced by isoprenaline was decreased in Homo rats at 21-23 weeks old compared with those in Hetero rats. The mRNA expression for α1A but not β2 adrenoreceptor in Homo rats was increased. Nitric oxide (NO)-mediated relaxation induced by acetylcholine was decreased, while the mRNA expression for endothelial NO synthase (eNOS) was rather increased in mesenteric artery from Homo rats. These findings for the first time revealed that in Homo rats with reduced plasma adrenaline, blood pressure could be maintained by enhancing vascular contractility induced by adrenaline through the increased α1 adrenoceptor expression and the attenuated β2 adrenoceptor signaling. Additionally, NO-mediated endothelium-dependent relaxation is impaired perhaps due to eNOS dysfunction, which might also contribute to maintain the blood pressure in Homo rats.

Dahl salt-sensitive (SS) rats fed a high-salt diet, but not low-salt, exhibit vascular dysfunction. Several substrains of SS rats exist that differ in their blood pressure phenotypes and salt sensitivity. The goal of this study was to investigate whether the John-Rapp-derived SS rat (SS/Jr), which exhibits spontaneous hypertension on a low-salt diet, presents with hallmarks of vascular dysfunction observed in another experimental model of hypertension independent of dietary salt, the spontaneously hypertensive rat (SHR). Endothelium-intact aortic rings and mesenteric resistance arteries were isolated from low-salt fed adult male SS/Jr rats and SHRs, or their respective controls, for isometric wire myography. Vessels were challenged with cumulative concentrations of various vasoactive substances, in the absence or presence of nitric oxide synthase or cyclooxygenase inhibitors. Despite showing some differences in their responses to various vasoactive substances, both SS/Jr rats and SHRs exhibited key features of vascular dysfunction, including endothelial dysfunction and hyperresponsiveness to vasocontractile agonists. In conclusion, this study provides evidence to support the utility of the SS/Jr rat strain maintained on a low-salt diet as a valid experimental model for vascular dysfunction, a key feature of human hypertension.

OBJECTIVE: The treatment of cardiovascular diseases (CVD) could greatly benefit from using nitric oxide (NO) donors. This study aimed to investigate the mechanisms of action of NONO2P that contribute to the observed responses in the mesenteric artery. The hypothesis was that NONO2P would have similar pharmacological actions to sodium nitroprusside (SNP) and NO.
METHODS: Male Wistar rats were euthanized to isolate the superior mesenteric artery for isometric tension recordings. NO levels were measured using the DAF-FM/DA dye, and cyclic guanosine monophosphate (cGMP) levels were determined using a cGMP-ELISA Kit.
RESULTS: NONO2P presented a similar maximum efficacy to SNP. The free radical of NO (NO•) scavengers (PTIO; 100 μM and hydroxocobalamin; 30 μM) and nitroxyl anion (NO-) scavenger (L-cysteine; 3 mM) decreased relaxations promoted by NONO2P. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor (ODQ; 10 μM) nearly abolished the vasorelaxation. The cGMP-dependent protein kinase (PKG) inhibition (KT5823; 1 μM) attenuated the NONO2P relaxant effect. The vasorelaxant response was significantly attenuated by blocking inward rectifying K+ channels (Kir), voltage-operated K+ channels (KV), and large conductance Ca2+-activated K+ channels (BKCa). NONO2P-induced relaxation was attenuated by cyclopiazonic acid (10 μM), indicating that sarcoplasmic reticulum Ca2+-ATPase (SERCA) activation is involved in this relaxation. Moreover, NONO2P increased NO levels in endothelial cells and cGMP production.
CONCLUSIONS: NONO2P induces vasorelaxation with the same magnitude as SNP, releasing NO• and NO-. Its vasorelaxant effect involves sGC, PKG, K+ channels opening, and SERCA activation, suggesting its potential as a therapeutic option for CVD.

Stimulation of the calcium-sensing receptor (CaSR) regulates vascular contractility, but cellular mechanisms involved remain unclear. This study investigated the role of perivascular sensory nerves in CaSR-induced relaxations of male rat mesenteric arteries. In fluorescence studies, colocalisation between synaptophysin, a synaptic vesicle marker, and the CaSR was present in the adventitial layer of arterial segments. Using wire myography, increasing external Ca2+ concentration ([Ca2+]o) from 1 to 10 mM induced vasorelaxations, previously shown to involve the CaSR, which were inhibited by pretreatment with capsaicin. [Ca2+]o-induced vasorelaxations were partially reduced by the calcitonin gene-related peptide (CGRP) receptor blockers, CGRP 8-37 and BIBN 4096, and the neurokinin 1 (NK1) receptor blocker L733,060. The inhibitory effect of CGRP 8-37 required a functional endothelium whereas the inhibitory action of L733,060 did not. Complete inhibition of [Ca2+]o-induced vasorelaxations occurred when CGRP 8-37 and L733,060 were applied together. [Ca2+]o-induced vasorelaxations in the presence of capsaicin were abolished by the ATP-dependent K+ channel (KATP) blocker PNU 37883, but unaffected by the endothelium nitric oxide synthase (eNOS) inhibitor L-NAME. We suggest that the CaSR on perivascular sensory nerves mediate relaxations in rat mesenteric arteries via endothelium-dependent and -independent mechanisms involving CGRP and NK1 receptor-activated NO production and KATP channels, respectively.

BACKGROUND: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment.
METHODS: Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence.
RESULTS: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels.
CONCLUSIONS: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.
Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease.

UNASSIGNED: Strongylus vulgaris is one of the most pathogenic nematodes affecting equids. Larval migration through the cranial mesenteric artery (CMA) with attendant arteritis and thromboembolism can result in fatal non-strangulating intestinal infarction. Once considered a historical disease, recent studies have described the reemergence of this pathogen in several European countries; however, little is known of the current prevalence of S. vulgaris in the Canadian horse population.
UNASSIGNED: To determine the prevalence of active S. vulgaris cranial mesenteric arteritis in horses submitted for postmortem examination to the Diagnostic Services Unit (DSU) at the University of Calgary Faculty of Veterinary Medicine.
UNASSIGNED: We conducted a retrospective review of all equine postmortem cases submitted to the DSU between July 1, 2010 and June 30, 2022. Over 12 y, 510 horses > 2 mo of age from Alberta were submitted to the DSU for necropsy. Active cases were defined as those with endarteritis and thrombosis in the CMA or its branches. Those cases with only intimal scarring of the CMA were classified as historical.
UNASSIGNED: The prevalence of all CMA lesions (both historical and active) over the study period was 17.3% (88/510). Active S. vulgaris cranial mesenteric arteritis was documented in 6.1% (31/510) of equine postmortems and the sequelae of verminous arteritis were the cause of euthanasia or death in 1.5% (8/510) of the cases submitted.
UNASSIGNED: Even after historically intense efforts to eradicate this parasite, the continued effects of S. vulgaris are demonstrated by the results of this study. Strongylus vulgaris should not be regarded as a parasite of the past and verminous arteritis remains an important differential diagnosis for horses in western Canada presenting with mild colic or dull demeanor and anorexia of duration > 24 h. Furthermore, S. vulgaris should be taken into careful consideration when implementing antiparasitic control strategies. Practitioners should remain current on prevention, diagnosis, and treatment of this potentially reemerging and fatal equine disease.
Étude rétrospective de la prévalence lors d’autopsies équines de l’artérite mésentérique crâniale causée par Strongylus vulgaris en Alberta (2010 à 2022).
UNASSIGNED: Strongylus vulgaris est l’un des nématodes les plus pathogènes affectant les équidés. La migration des larves à travers l’artère mésentérique crâniale (CMA), accompagnée d’artérite et de thromboembolie, peut entraîner un infarctus intestinal non étranglant mortel. Autrefois considérée comme une maladie historique, des études récentes ont décrit la réémergence de cet agent pathogène dans plusieurs pays européens; cependant, on sait peu de choses sur la prévalence actuelle de S. vulgaris dans la population équine canadienne.
UNASSIGNED: Déterminer la prévalence de l’artérite mésentérique crâniale active à S. vulgaris chez les chevaux soumis pour examen post mortem au Diagnostic Service Unit (DSU), College of Veterinary Medicine, University of Calgary.
UNASSIGNED: Nous avons effectué un examen rétrospectif de tous les cas post-mortem d’équidés soumis au DSU entre le 1er juillet 2010 et le 30 juin 2022. Sur 12 ans, 510 chevaux âgés de plus de 2 mois de l’Alberta ont été soumis au DSU pour autopsie. Les cas actifs ont été définis comme ceux présentant une endartérite et une thrombose dans la CMA ou ses branches. Les cas présentant uniquement des cicatrices à l’intima de la CMA ont été classés comme anciens.
UNASSIGNED: La prévalence de toutes les lésions de CMA (anciennes et actives) au cours de la période d’étude était de 17,3 % (88/510). Une artérite mésentérique crâniale active à S. vulgaris a été documentée dans 6,1 % (31/510) des autopsies équines et les séquelles de l’artérite vermineuse ont été la cause de l’euthanasie ou du décès dans 1,5 % (8/510) des cas soumis.
UNASSIGNED: Malgré des efforts historiquement intenses pour éradiquer ce parasite, les effets continus de S. vulgaris sont démontrés par les résultats de cette étude. Strongylus vulgaris ne doit pas être considéré comme un parasite du passé et l’artérite vermineuse demeure un diagnostic différentiel important pour les chevaux de l’ouest du Canada présentant des coliques légères ou un comportement abattu et une anorexie de durée > 24 h. De plus, S. vulgaris doit être attentivement pris en compte lors de la mise en œuvre de stratégies de contrôle antiparasitaire. Les praticiens doivent rester informés de la prévention, du diagnostic et du traitement de cette maladie équine potentiellement ré-émergente et mortelle.(Traduit par Dr Serge Messier).

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease (COPD) but was recently found to possess broad-spectrum off-target effects. Here, we show that, under physiological Ca2+ (200-500 nM) and voltages, niclosamide acutely potentiates TMEM16A. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering clinical applications of niclosamide as a TMEM16A inhibitor. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation and provides insights into developing specific TMEM16A modulators to treat human diseases.

OBJECTIVE: This study aimed to report the initial experience with a novel bidirectional double cuff inner branch design for incorporation of renal and mesenteric arteries in patients undergoing fenestrated and branched endovascular aortic repair (F/BEVAR).
METHODS: A retrospective review was undertaken of the experience of F/BEVAR with grafts integrating at least one bidirectional double cuffed inner branch implanted at three tertiary aortic centres between March 2022 and June 2023. All consecutive patients were included. Baseline characteristics, operative data, and follow up data were collected. Results were presented as number or median (interquartile range) unless otherwise stated.
RESULTS: Thirteen patients (10 male; median age 72 [68, 77] years) had F/BEVAR using a total of 15 bidirectional double cuffed inner branches (30 cuffs). Indications for bidirectional doubled cuffed inner branches included cranial vessel orientation or double renal arteries in four patients each, common coeliomesenteric trunk in three patients, and early renal artery bifurcation, renal artery origin from a false lumen requiring a flexible route for catheterisation, and surplus configuration in one patient each. Twenty three of the 30 cuffs were used, whereas the remaining seven cuffs were intentionally occluded with vascular plugs. Target vessel incorporation was successful in all bidirectional branches. There was one technical failure related to unsuccessful catheterisation of a left renal artery targeted through a unidirectional caudal inner branch. During a median follow up of seven months there were no instances of target vessel instability or re-interventions and two patients died of causes unrelated to the bidirectional branches.
CONCLUSIONS: The results of the use of bidirectional double cuff inner branches are promising, with high technical success and no short term branch related complications in this preliminary experience. This could potentially expand the applicability of branch endografting of complex endovascular aortic repairs, but long term results are still missing.

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UNASSIGNED: GPCRs (G-protein-coupled receptors) play a central role in the regulation of smooth muscle cell (SMC) contractility, but the function of SMC-expressed orphan GPCR class C group 5 member C (GPRC5C) is unclear. The aim of this project is to define the role of GPRC5C in SMC in vitro and in vivo.
UNASSIGNED: We studied the role of GPRC5C in the regulation of SMC contractility and differentiation in human and murine SMC in vitro, as well as in tamoxifen-inducible, SMC-specific GPRC5C knockout mice under basal conditions and in vascular disease in vivo.
UNASSIGNED: Mesenteric arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed ex vivo significantly reduced angiotensin II (Ang II)-dependent calcium mobilization and contraction, whereas responses to other relaxant or contractile factors were normal. In vitro, the knockdown of GPRC5C in human aortic SMC resulted in diminished Ang II-dependent inositol phosphate production and lower myosin light chain phosphorylation. In line with this, tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed reduced Ang II-induced arterial hypertension, and acute inactivation of GPRC5C was able to ameliorate established arterial hypertension. Mechanistically, we show that GPRC5C and the Ang II receptor AT1 dimerize, and knockdown of GPRC5C resulted in reduced binding of Ang II to AT1 receptors in HEK293 cells, human and murine SMC, and arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice.
UNASSIGNED: Our data show that GPRC5C regulates Ang II-dependent vascular contraction by facilitating AT1 receptor-ligand binding and signaling.