A retrospective study of the prevalence in equine postmortems of cranial mesenteric arteritis caused by Strongylus vulgaris in Alberta (2010 to 2022).

Background: 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. Objective: 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. Animals and procedure: 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. Results: 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. Conclusion and clinical relevance: 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). Contexte: 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. Objectif: 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. Animaux et procédure: 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. Résultats: 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. Conclusion et pertinence clinique: 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).

Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling.

Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT1 receptors and NADPH oxidase, and lower expression of AT2, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.

[EVALUATION OF SYSTEMIC PRO-INFLAMMATORY REACTIONS IN SIMULATING REVERSIBLE OCCLUSION OF ANTERIOR MESENTERIC ARTERY TO JUSTIFY MEDICAL REHABILITATION].

The purpose of the work was to analyze the pro-inflammatory reaction caused by different duration of ischemic-reperfusion of intestinal damage in occlusion of anterior mesenteric artery in the experiment. Ischemic reperfusion damage of the intestinal wall was simulated using reversible occlusion of the anterior mesenteric artery with 30 rats. Two types of operations were carried out: operation 1 - the duration of ischemia 20 minutes, reperfusion - 40 minutes, operation 2 - 30 and 30 minutes, respectively. Four groups were formed by simple sampling: the first - false-operated animals (n=5), the second - model-operation 1 (n=8), the third - model-operation 2 (n=6), the 4th - control group (n=7). Lactate level was determined by BM-Lactat test strips and the number of blood leukocytes was calculated before and after the surgery. During the postoperative period, interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), monocytic chemotoxic factor-1 (MCF-1) in serum were determined. In groups 2 and 3 it was established: a decrease in leukocytes in peripheral blood by 15-20% and an increase in lactate level by 20-120% during the postoperative period with the establishment of direct statistically significant connections between the number of leukocytes in the blood and lactate content (r=+0.83, p=0.01); between the number of leukocytes in the blood and IL-1ß blood level (r=+0.96; p=0,00002); reduction of IL-1ß level in blood with the animals of group 3 as compared with false-operated and MCF-1 level with the animals of group 2 as compared with false-operated, which may be related to the influence of corrective action of anti-inflammatory response. The increase of TNF-a level with the animals of the second group by 1.5-2 times and in the third group by 3 times compared to false-operated animals, which is the most significant manifestation of pro-inflammatory response to ischemia/reperfusion, depends on the degree of the damage due to the duration of ischemic period. The development of systemic pro-inflammatory reactions in the simulation of reversible occlusion of anterior mesenteric artery is the basis for the rehabilitation of patients after various surgical interventions in the intestine in order to prevent abdominal postoperative complications.

Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice.

Recent studies have shown that chronic use of prescription or illicit opioids leads to an increased risk of cardiovascular events and pulmonary arterial hypertension. Indices of vascular age and arterial stiffness are also shown to be increased in opioid-dependent patients, with the effects being more marked in women. There are currently no studies investigating sex-specific vascular dysfunction in opioid use, and the mechanisms leading to opioid-induced vascular damage remain unknown. We hypothesized that exposure to exogenous opioids causes sex-specific vascular remodeling that will be more pronounced in female. Acknowledging the emerging roles of cofilins and extracellular signal-regulated kinases (ERKs) in mediating actin dynamics, we investigated the effects of morphine on these molecules. Twenty-four hour exposure to morphine increased inactivated cofilin and activated ERKs in resistance arteries from female mice, which may promote stress fiber over-assembly. We also performed continuous intraluminal infusion of morphine in pressurized resistance arteries from male and female mice using culture pressure myographs. We observed that morphine reduced the vascular diameter in resistance arteries from female, but not male mice. These results have significant implications for the previously unexplored role of exogenous opioids as a modifiable cardiovascular risk factor, especially in women.

Retrograde Open Mesenteric Stenting for Acute and Chronic Mesenteric Ischaemia: Results from an Intestinal Stroke Centre.

OBJECTIVE: To report the intra-operative adverse events (IOAEs) and the initial and one year outcomes of retrograde open mesenteric stenting (ROMS) using balloon expandable covered stents for acute and chronic mesenteric ischaemia. METHODS: Clinical data and outcomes of all consecutive patients treated with ROMS for acute and chronic mesenteric ischaemia at an intestinal stroke centre between November 2012 and September 2019 were reviewed. ROMS was performed using balloon expandable covered stents. Endpoints included IOAEs, in hospital mortality, post-operative complications, and re-interventions. One year overall survival, freedom from re-intervention, primary patency and assisted primary patency rates were analysed using the Kaplan-Meier time to event method. RESULTS: During the study period, 379 patients were referred to the centre for acute or chronic mesenteric ischaemia. Thirty-seven patients who underwent the ROMS procedure were included. All the patients had severe atherosclerotic mesenteric lesions. The ROMS technical success rate was 89% in this cohort. The rate of IOAEs was 19% and included four cases of retrograde recanalisation failure. All ROMS failures occurred in patients presenting with flush superior mesenteric artery occlusion and they were treated by mesenteric bypass. Ten patients (27%) underwent bowel resection, four of which resulted in a short bowel syndrome (11%). The in hospital mortality rate was 27%. Post-operative complications and re-intervention rates were 67% (n = 25) and 32% (n = 12), respectively. The median follow up was 20.2 months (interquartile range 29). The estimated one year overall survival for the cohort was 70.1% (95% confidence interval [CI] 52.5% - 82.2%). The estimated freedom from re-intervention at one year was 61.1% (95% CI 42.3 - 75.4). The one year primary patency and assisted primary patency rates were 84.54% (95% CI 63.34 - 94) and 92.4% (95% CI 72.8 - 98), respectively. CONCLUSION: ROMS procedures offer acceptable one year outcomes for mesenteric ischaemia but are associated with frequent stent related complications. Precise pre-operative planning, high quality imaging, and meticulous stent placement techniques may limit the occurrence of such events.

Diminazene Aceturate Stabilizes Atherosclerotic Plaque and Attenuates Hepatic Steatosis in apoE-Knockout Mice by Influencing Macrophages Polarization and Taurine Biosynthesis.

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE-/- mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.

Prenatal hypoxia inhibited propionate-evoked BK channels of mesenteric artery smooth muscle cells in offspring.

As a common complication of pregnancy, gestational hypoxia has been shown to predispose offspring to vascular dysfunction. Propionate, one of short-chain fatty acids, exerts cardioprotective effects via reducing blood pressure. This study examined whether prenatal hypoxia impaired propionate-stimulated large-conductance Ca2+ -activated K+ (BK) channel activities in vascular smooth muscle cells (VSMCs) of offspring. Pregnant rats were exposed to hypoxia (10.5% oxygen) and normoxia (21% oxygen) from gestational day 7-21. At 6 weeks of age, VSMCs in mesenteric arteries of offspring were analysed for BK channel functions and gene expressions. It was shown firstly that propionate could open significantly BK single channel in VSMCs in a concentration-dependent manner. Antagonists of G protein ßγ subunits and inositol trisphosphate receptor could completely suppress the activation of BK by propionate, respectively. Gαi/o and ryanodine receptor were found to participate in the stimulation on BK. Compared to the control, vasodilation and increments of BK NPo (the open probability) evoked by propionate were weakened in the offspring by prenatal hypoxia with down-regulated Gßγ and PLCß. It was indicated that prenatal hypoxia inhibited propionate-stimulated BK activities in mesenteric VSMCs of offspring via reducing expressions of Gßγ and PLCß, in which endoplasmic reticulum calcium release might be involved.

Aging alters spontaneous and neurotransmitter-mediated Ca2+ signaling in smooth muscle cells of mouse mesenteric arteries.

OBJECTIVE: Aging impairs MA dilation by reducing the ability of sensory nerves to counteract sympathetic vasoconstriction. This study tested whether altered SMC Ca2+ signals to sympathetic (NE) and sensory (CGRP) neurotransmitters underlie aging-related deficits in vasodilation. METHODS: MAs from young and old mice were pressurized and loaded with Fluo-4 dye for confocal measurement of SMC Ca2+ sparks and waves. Endothelial denudation resolved the influence of ECs. SMCs were immunolabeled for RyR isoforms and compared with transcript levels for RyRs and CGRP receptor components. RESULTS: SMCs from young vs old mice exhibited more spontaneous Ca2+ spark sites with no difference in Ca2+ waves. NE reduced spark sites and increased waves for both groups; addition of CGRP restored sparks and reduced waves only for young mice. Endothelial denudation attenuated Ca2+ responses to CGRP for young but not old mice, which were already attenuated, suggesting a diminished role for ECs with aging. CGRP receptor expression was similar between ages with increased serum CGRP in old mice, where RyR1 expression was replaced by RyR3. CONCLUSION: With aging, we suggest that altered RyR expression in SMCs contributes to impaired ability of sensory neurotransmission to restore Ca2+ signaling underlying vasomotor control during sympathetic activation.

Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America.

OBJECTIVES: To develop and replicate, using data-driven methods, a novel classification system in Takayasu's arteritis based on distribution of arterial lesions. METHODS: Patients were included from four international cohorts at major academic centres: India (Christian Medical College Vellore); North America (National Institutes of Health, Vasculitis Clinical Research Consortium and Cleveland Clinic Foundation). All patients underwent whole-body angiography of the aorta and branch vessels, with categorization of arterial damage (stenosis, occlusion or aneurysm) in 13 territories. K-means cluster analysis was performed to identify subgroups of patients based on pattern of angiographic involvement. Cluster groups were identified in the Indian cohort and independently replicated in the North American cohorts. RESULTS: A total of 806 patients with Takayasu's arteritis from India (n = 581) and North America (n = 225) were included. Three distinct clusters defined by arterial damage were identified in the Indian cohort and replicated in each of the North American cohorts. Patients in cluster one had significantly more disease in the abdominal aorta, renal and mesenteric arteries (P < 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P < 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P < 0.01). Demographics, clinical symptoms and clinical outcomes differed by cluster. CONCLUSION: This large study in Takayasu's arteritis identified and replicated three novel subsets of patients based on patterns of arterial damage. Angiographic-based disease classification requires validation by demonstrating potential aetiological or prognostic implications.

Finerenone Reduces Intrinsic Arterial Stiffness in Munich Wistar Frömter Rats, a Genetic Model of Chronic Kidney Disease.

BACKGROUND: Development of albuminuria and arterial stiffness in Munich Wistar Frömter (MWF) rats, a model of chronic kidney disease, is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction. Finerenone (FIN), a novel, nonsteroidal, potent, and selective mineralocorticoid receptor antagonist, improves endothelial dysfunction through enhancing nitric oxide (NO) bioavailability and decreasing superoxide anion levels due to an upregulation in vascular and renal superoxide dismutase activity. We hypothesize that FIN reduces arterial stiffness in this model associated to the reduction in albuminuria and matrix metalloproteinase (MMP)-2/9 activity. METHODS: Twelve-week-old MWF rats with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated with FIN (10 mg/kg/day, once-daily oral gavage) or with vehicle (control, C) for 4 weeks. RESULTS: Arterial stiffness was significantly higher in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN treatment significantly lowered ß-index, a measure of intrinsic stiffness independent of geometry, in MWF (ßMWF-FIN = 7.7 ± 0.4 vs. ßMWF-C = 9.2 ± 0.5, p < 0.05) positively correlating with urinary albumin excretion. Elastin fenestrae area in the internal elastic lamina of MA from MWF-FIN was significantly larger (+377%, p < 0.05). FIN increased plasma pro-MMP-2 and decreased plasma MMP-2 and MMP-9 activities, correlating with reductions in ß-index. MA from MWF-FIN exhibited higher NO bioavailability and reduced superoxide anion levels compared to MWF-C. CONCLUSION: FIN treatment reduces intrinsic arterial stiffness in MA from MWF rats associated with changes in elastin organization, normalization of MMP-2 and MMP-9 activities, and reduction of oxidative stress. Moreover, reduction of arterial stiffness correlates with reduction in albuminuria.

TP and/or EP3 receptors mediate the vasoconstrictor and pressor responses of prostaglandin F2α in mice and/or humans.

The vasoconstrictor and/or pressor effects of prostaglandin (PG)F2α participate in the development of vascular pathologies and limit the clinical use of the agent. This study aimed to determine the receptor types responsible for the vasoconstrictor activity of PGF2α and whether they mediate the pressor response evoked by the prostanoid under in vivo conditions. Experiments were performed on genetically altered mice and/or on vessels from these mice or humans. Here we show that deletion of the thromboxane-prostanoid receptor (TP-/-) abolished or drastically diminished the contraction to PGF2α in isolated mouse vessels (some of which were resistance arteries) and reduced the elevation in blood pressure evoked by the prostanoid under in vivo conditions. In accordance, TP antagonism abolished the contraction in small arteries of human omentum. Further deletion of E prostanoid receptor type 3 (EP3-/-) removed the PGF2α-evoked contraction that remained in some TP-/- arteries and added to the effect of TP-/- on the elevation in blood pressure evoked by the prostanoid under in vivo conditions. In contrast, the uterine contraction to PGF2α mediated via the F prostanoid receptor (FP) was unaltered in TP-/-/EP3-/- mice. These results demonstrate that the non-FP receptors TP and/or EP3 mediate the vasoconstrictor and pressor effects of PGF2α, which are still of concern under clinical conditions.-Liu, B., Li, J., Yan, H., Tian, D., Li, H., Zhang, Y., Guo, T., Wu, X., Luo, W., Zhou, Y. TP and/or EP3 receptors mediate the vasoconstrictor and pressor responses of prostaglandin F2α in mice and/or humans.

Radiographic portal or superior mesenteric vein invasion is an independent prognostic factor in non-metastatic pancreatic ductal adenocarcinoma: A missing block of clinical T staging?

BACKGROUND: Venous invasion is not included in the pancreatic ductal adenocarcinoma (PDAC) staging, and its correlation with prognosis remains unclear. We evaluated the prognostic impact of radiographic portal/superior mesenteric vein (PV/SMV) invasion, and its possibility of complementing T staging. METHODS: We identified patients with non-metastatic PDAC using our institutional cohort, and divided them according to PV/SMV invasion at imaging, defined as >180-degree tumor-vessel interface or contour deformity. We conducted Cox proportional hazard regression, and compared survival in the original and 1:1 propensity score matched datasets. RESULTS: We identified 454 patients [PV/SMV(+): 172; PV/SMV(-): 282]. In the multivariate analysis, PV/SMV invasion, age (≥70 years), performance status, tumor size (2-4, >4 cm), lymph nodes >4, and arterial invasion was correlated with prognosis. The PV/SMV(+) group had a shorter overall survival (OS) than the PV/SMV(-) group in the original (14.4 vs. 20.9 months; P < 0.001) and matched datasets (14.3 vs. 17.2 months; P = 0.009). Among patients without arterial invasion (cT1-cT3), the PV/SMV(+) group had a shorter OS (15.9 vs. 21.2 months; P = 0.002). Moreover, their OS did not differ from that of patients with arterial invasion (cT4) (15.9 vs. 14.4 months; P = 0.907). Patients with vessel (artery/vein) invasion had a shorter OS than those without vessel invasion (14.5 vs. 21.2 months; P < 0.001). CONCLUSIONS: Radiographic PV/SMV invasion in non-metastatic PDAC was correlated with a poor prognosis. It could identify a group with shorter OS among patients without arterial invasion (cT1-cT3). It is suggested that inclusion of PV/SMV invasion in clinical T4 criteria should be considered.

Cellular and molecular events of inflammation induced transdifferentiation (EMT) and regeneration (MET) in mesenteric mesothelial cells.

In this review we summarize the cellular and molecular events of inflammation induced epithelial-to-mesenchymal (EMT) and mesothelial-to-macrophage transition (MET) during regeneration. Since the receptor transmits the environmental stimulus, downregulating or upregulating the process on an epigenetic level, the intracellular localization of receptors (signaling organelles: early endosomes or lysosomal degradation: late endosomes) plays a crucial role in the signaling events regulating inflammation and regeneration. Therefore, we focused on the internalization of the receptors as well as the intracellular compartmentalization of signaling molecules during EMT and MET. The review draws the reader's attention to the plasticity of mesothelial cells and supports the idea that during inflammation an ambient macrophage population might derive from mesothelial cells.

Short-term outcomes after vascular resection for pancreatic tumors: Lessons learned from 72 cases from a single Brazilian Cancer Center.

INTRODUCTION: Pancreatic malignant tumors are resectable at diagnosis in only 15% to 20% of cases and invasion of vascular structures is commonly present. Therefore, extended resections are needed for adequate local control and negative margins. However, morbidity and mortality associated with these enlarged resections are limiting factors. The aim of this study was to correlate demographic and technical aspects that influenced early and late outcomes. MATERIALS AND METHODS: Between October 2007 and May 2019, 523 pancreatic surgeries were performed, of which 72 required vascular resections. Clinical and histopathological data, surgical techniques, and perioperative parameters were analyzed in a prospectively collected database. RESULTS: Of the 72 cases of vascular resection, 31 were male and 41 females with a mean age of 60.9 years (34-81). The most commonly affected vascular structure was the portal vein (in 40.3%). Free margins were obtained in 77.8% of cases. Postoperative mortality rate at 60 days was 13.9%. American Society of Anesthesiologists (ASA) and age were the most important predictors of major complications. CONCLUSION: Extended resections with vascular involvement in pancreatic surgeries are feasible and safe; furthermore, patient selection plays are key. ASA and age were the most important factors in the decision-making process for extended resections.

Aberrant Mesenteric Migration of Spirocerca lupi Larvae Causing Necrotizing Eosinophilic Arteritis, Thrombosis, and Intestinal Infarction in Dogs.

This report presents a novel canine condition in 32 dogs in which aberrant migration of Spirocerca lupi larvae through mesenteric arteries, instead of gastric arteries, led to small or large intestinal infarction. This form of spirocercosis was first recognized in Israel in 2013 and is currently ongoing. Typical clinical signs were anorexia and weakness of 3 to 4 days and, less frequently, vomiting and diarrhea, followed by collapse, bloody diarrhea, and severe vomiting. Exploratory laparotomy showed 1 or more infarcted and often perforated intestinal segments in all cases. Microscopically, there was intestinal mucosal to transmural coagulative necrosis and mesenteric multifocal necrotizing eosinophilic arteritis, thrombosis, hemorrhage, and early fibroplasia. Third-stage S. lupi larvae were identified by morphologic features in 9 of 32 (28%) cases, and the species was confirmed by polymerase chain reaction in 4 cases. Nearly 50% of the dogs had been receiving prophylactic therapy, which did not prevent this form of spirocercosis.

Prenatal hypoxia plus postnatal high-fat diet exacerbated vascular dysfunction via up-regulated vascular Cav1.2 channels in offspring rats.

BACKGROUND: This study aimed to examine whether and how postnatal high-fat diet had additional impact on promoting vascular dysfunction in the offspring exposed to prenatal hypoxia. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were randomly assigned to hypoxia (10.5% oxygen) or normoxia (21% O2 ) groups from gestation days 5-21. A subset of male offspring was placed on a high-fat diet (HF, 45% fat) from 4-16 weeks of age. Prenatal hypoxia induced a decrease in birth weight. In offspring-fed HF diet, prenatal hypoxia was associated with increased fasting plasma triglyceride, total cholesterol, free fatty acids, and low-density lipoprotein-cholesterol. Compared with the other three groups, prenatal hypoxic offspring with high-fat diet showed a significant increase in blood pressure, phenylephrine-mediated vasoconstrictions, L-type voltage-gated Ca2+ (Cav1.2) channel currents, and elevated mRNA and protein expression of Cav1.2 α1 subunit in mesenteric arteries or myocytes. The large-conductance Ca2+-activated K+ (BK) channels currents and the BK channel units (ß1, not α-subunits) were significantly increased in mesenteric arteries or myocytes in HF offspring independent of prenatal hypoxia factor. CONCLUSION: The results demonstrated that prenatal hypoxia followed by postnatal HF caused vascular dysfunction through ion channel remodelling in myocytes.

Reconstitution of autophagy ameliorates vascular function and arterial stiffening in spontaneously hypertensive rats.

Insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of dysfunctional macromolecules and organelles. Premature vascular aging occurs in hypertension. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in clinical and experimental hypertension. Previously, we have reported decreased autophagy in arteries from spontaneously hypertensive rats (SHRs); however, the effects of restoring autophagic activity on blood pressure and vascular function are currently unknown. We hypothesized that reconstitution of arterial autophagy in SHRs would decrease blood pressure and improve endothelium-dependent relaxation. We treated 14- to 18-wk-old Wistar rats (n = 7 vehicle and n = 8 trehalose) and SHRs (n = 7/group) with autophagy activator trehalose (2% in drinking water) for 28 days. Blood pressure was measured by radiotelemetry, and vascular function and structure were measured in isolated mesenteric resistance arteries (MRAs) using wire and pressure myographs, respectively. Treatment with trehalose had no effect on blood pressure in SHRs; however, isolated MRAs presented enhanced relaxation to acetylcholine, in a cyclooxygenase- and reactive oxygen species-dependent manner. Similarly, trehalose treatment shifted the relaxation to the Rho kinase (ROCK) inhibitor Y-27632 to the right, indicating reduced ROCK activity. Finally, trehalose treatment decreased arterial stiffness as indicated by the slope of the stress-strain curve. Overall these data indicate that reconstitution of arterial autophagy in SHRs improves endothelial and vascular smooth muscle function, which could synergize to prevent stiffening. As a result, restoration of autophagic activity could be a novel therapeutic for premature vascular aging in hypertension.NEW & NOTEWORTHY This work supports the concept that diminished arterial autophagy contributes to premature vascular aging in hypertension and that therapeutic reconstitution of autophagic activity can ameliorate this phenotype. As vascular age is a new clinically used index for cardiovascular risk, understanding this mechanism may assist in the development of new drugs to prevent premature vascular aging in hypertension.

Extracellular histones induce calcium signals in the endothelium of resistance-sized mesenteric arteries and cause loss of endothelium-dependent dilation.

Histone proteins are elevated in the circulation after traumatic injury owing to cellular lysis and release from neutrophils. Elevated circulating histones in trauma contribute to coagulopathy and mortality through a mechanism suspected to involve endothelial cell (EC) dysfunction. However, the functional consequences of histone exposure on intact blood vessels are unknown. Here, we sought to understand the effects of clinically relevant concentrations of histones on the endothelium in intact, resistance-sized, mesenteric arteries (MAs). EC Ca2+ was measured with high spatial and temporal resolution in MAs from mice selectively expressing the EC-specific, genetically encoded ratiometric Ca2+ indicator, Cx40-GCaMP-GR, and vessel diameter was measured by edge detection. Application of purified histone protein directly to the endothelium of en face mouse and human MA preparations produced large Ca2+ signals that spread within and between ECs. Surprisingly, luminal application of histones had no effect on the diameter of pressurized arteries. Instead, after prolonged exposure (30 min), it reduced dilations to endothelium-dependent vasodilators and ultimately caused death of ~25% of ECs, as evidenced by markedly elevated cytosolic Ca2+ levels (793 ± 75 nM) and uptake of propidium iodide. Removal of extracellular Ca2+ but not depletion of intracellular Ca2+ stores prevented histone-induced Ca2+ signals. Histone-induced signals were not suppressed by transient receptor potential vanilloid 4 (TRPV4) channel inhibition (100 nM GSK2193874) or genetic ablation of TRPV4 channels or Toll-like receptor receptors. These data demonstrate that histones are robust activators of noncanonical EC Ca2+ signaling, which cause vascular dysfunction through loss of endothelium-dependent dilation in resistance-sized MAs. NEW & NOTEWORTHY We describe the first use of the endothelial cell (EC)-specific, ratiometric, genetically encoded Ca2+ indicator, Cx40-GCaMP-GR, to study the effect of histone proteins on EC Ca2+ signaling. We found that histones induce an influx of Ca2+ in ECs that does not cause vasodilation but instead causes Ca2+ overload, EC death, and vascular dysfunction in the form of lost endothelium-dependent dilation.

High Sodium Intake Impairs Small Artery Vasoreactivity in vivo in Dahl Salt-Sensitive Rats.

The effects of high sodium intake on the functionality of resistance arteries have been repeatedly studied in vitro, but no study has focused on salt-sensitive hypertension in vivo. We studied the in vivo reactivity of mesenteric small arteries (MSAs) to vasoactive agents in Dahl salt-sensitive (DS) rats with various sodium diets. Twenty-four male DS rats were randomized into 3 groups: LS (0.3% NaCl diet), NS (0.6% NaCl diet), and HS (8% NaCl diet). After a 12-week intervention, the diameter changes of the MSAs after noradrenaline (NA) and acetylcholine (ACh) exposure were detected by a microscope, and changes in blood perfusion through the MSAs were measured by full-field laser perfusion imaging. HS enhanced the constrictive response of the MSAs to NA and attenuated the relaxing response to ACh. Low sodium intake reduced the response of the MSAs to NA and promoted ACh-induced vasodilatation. HS also aggravated NA-induced blood perfusion reduction and impaired ACh-induced hyperperfusion of the MSAs. Pathologically, HS was associated with arteriolar structural damage and fibrosis of the MSAs. We conclude that sodium intake affects the responsiveness of the MSAs to vasoactive agents in DS rats and might play important roles in modulating blood pressure in hypertensive individuals.

Loss of Vascular Myogenic Tone in miR-143/145 Knockout Mice Is Associated With Hypertension-Induced Vascular Lesions in Small Mesenteric Arteries.

OBJECTIVE: Pressure-induced myogenic tone is involved in autoregulation of local blood flow and confers protection against excessive pressure levels in small arteries and capillaries. Myogenic tone is dependent on smooth muscle microRNAs (miRNAs), but the identity of these miRNAs is unclear. Furthermore, the consequences of altered myogenic tone for hypertension-induced damage to small arteries are not well understood. APPROACH AND RESULTS: The importance of smooth muscle-enriched microRNAs, miR-143/145, for myogenic tone was evaluated in miR-143/145 knockout mice. Furthermore, hypertension-induced vascular injury was evaluated in mesenteric arteries in vivo after angiotensin II infusion. Myogenic tone was abolished in miR-143/145 knockout mesenteric arteries, whereas contraction in response to calyculin A and potassium chloride was reduced by ≈30%. Furthermore, myogenic responsiveness was potentiated by angiotensin II in wild-type but not in knockout mice. Angiotensin II administration in vivo elevated systemic blood pressure in both genotypes. Hypertensive knockout mice developed severe vascular lesions characterized by vascular inflammation, adventitial fibrosis, and neointimal hyperplasia in small mesenteric arteries. This was associated with depolymerization of actin filaments and fragmentation of the elastic laminae at the sites of vascular lesions. CONCLUSIONS: This study demonstrates that miR-143/145 expression is essential for myogenic responsiveness. During hypertension, loss of myogenic tone results in potentially damaging levels of mechanical stress and detrimental effects on small arteries. The results presented herein provide novel insights into the pathogenesis of vascular disease and emphasize the importance of controlling mechanical factors to maintain structural integrity of the vascular wall.