Single-Cell Mapping of Large and Small Arteries During Hypertensive Aging.

Vascular aging is directly related to several major diseases including clinical primary hypertension. Conversely, elevated blood pressure itself accelerates vascular senescence. However, the interaction between vascular aging and hypertension has not been characterized during hypertensive aging. To depict the interconnectedness of complex mechanisms between hypertension and aging, we performed single-cell RNA sequencing of aorta, femoral and mesentery arteries, respectively, from male Wistar Kyoto rats and male spontaneously hypertensive rats aging 16 or 72 weeks. We integrated 12 data sets to map the blood vessels of senile hypertension from 3 perspective: vascular aging, hypertension, and vascular type. We found that aging and hypertension independently exerted a significant impact on the alteration of cellular composition and artery remodeling, even greater when superimposed. Consistently, smooth muscle cells (SMCs) underwent phenotypic switching from contractile toward synthetic, apoptotic, and senescent SMCs with aging/hypertension. Furthermore, we identified 3 subclusters of Spp1high, encoding protein osteopontin (OPN), synthetic SMCs, Spp1high matrix activated fibroblasts, and Spp1high scar-associated macrophage involved in hypertensive aging. Spp1high scar-associated macrophage enriched for reactive oxygen species metabolic process and cell migration-associated function. Cell-cell communication analysis revealed Spp1-Cd44 receptor pairing was markedly aggravated in the hypertensive aging condition. Importantly, the concentration of serum OPN significantly potentiated in aged hypertensive patients compared with the normal group. Thus, we provide a comprehensive cell atlas to systematically resolve the cellular diversity and dynamic cellular communication changes of the vessel wall during hypertensive aging, identifying a protein marker OPN as a potential regulator of vascular remodeling during hypertensive aging.

Cysteamine Attenuate Intestinal Reperfusion Injury Induced by Occlusion of Mesenteric Artery by Enhancing Intracellular Thiol Activities.

BACKGROUND: Ischemia/reperfusion has been reported to further damage the intestine reperfusion injury (IRI) and cause multiple distal organ dysfunction through oxidative stress, inflammation, and apoptosis. Cysteamine is known to inhibit oxidative stress, inflammatory cytokines and apoptosis. This experiment was designed to evaluate the role of cysteamine against IRI in rats METHODS: Thirty-two Wistar rat strains were assigned to four groups: sham, Intestinal-reperfusion injury (IRI), 50 mg/kg and 100 mg/kg cysteamine treatment IRI. A 5 cm segment of terminal ileum was twisted 360° clockwise along the mesentery for 45 minutes to induce ischemia before detorsion. Tissues were preserved for biochemical evaluation and histology 4 hours after detorsion. Activities of GPx, GSH, protein and non-protein thiol, H2O2, MDA were evaluated. Serum concentration of nitrite, MPO, ALT, AST TNF-alpha and IL-6 were measured. Caspase 3 and bax were evaluated by immunohistochemistry. Statistical significance was set as p<0.05 RESULTS: Significant (p<0.05) increase in H2O2, MDA and nitrite but reduction in GPx, GSH, protein thiol and non-protein thiol in the IRI rats was reversed by 50 and 100 mg/kg cysteamine. Serum MPO, TNF-α, IL6, AST and ALT was significantly elevated in IRI while the rats treated with cysteamine showed a significant decrease (p<0.05) in the activities of these inflammatory and hepatic injury markers. CONCLUSION: Cysteamine mitigate IRI by enhancing intracellular antioxidant defense system, inhibiting inflammatory mediators and intestinal tissue expression of pro-apoptotic protein.

[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.

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.

Influenza A Virus Causes Histopathological Changes and Impairment in Functional Activity of Blood Vessels in Different Vascular Beds.

It has been established that blood vessels are a target for influenza virus; however, the mechanism by which virus affects the cardiovascular system remains unknown. The aim of the study is the identification of histological changes and changes in the functional activity of the pulmonary and mesenteric blood vessels of Wistar rats. Wistar rats were intranasally infected with the influenza A(H1N1)pdm09 virus. At 24 and 96 h post infection (hpi), histopathological changes were observed in lung tissues with the absence of histological changes in mesenteric tissues. The functional activity of pulmonary and mesenteric arteries was determined using wire myography. In pulmonary arteries, there was a tendency towards an increase in integral response to the vasodilator and a decrease in the integral response to the vasoconstrictor at 24 hpi (compared with control). At 96 hpi, a tendency towards a decrease in the integral response to the vasoconstrictor persisted, while the response to acetylcholine was slightly increased. The functional activity of the mesenteric blood vessels was inverted: a significant decrease in the integral response to the vasodilator and an increase in the response to the vasoconstrictor at 24 hpi were observed; at 96 hpi, the integral response to the vasoconstrictor persisted, while the response to the vasodilator remained significantly reduced. Obtained data indicate the development of endothelial dysfunction in non-lethal and clinically non-severe experimental influenza virus infection.

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.

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.

Fatal hemoperitoneum due to rupture of mesenteric artery in remission state of microscopic polyangiitis, concomitant with severe hypertension and posterior reversible encephalopathy syndrome: an autopsy case report.

Microscopic polyangiitis (MPA) is a type of necrotizing vasculitis associated with high levels of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). While generally associated with renal dysfunction, MPA can also cause intraabdominal hemorrhage in rare cases. A 66-year-old man was admitted to our hospital for renal dysfunction, numbness, and weight loss for 3 months. He had no significant medical history. Renal biopsy revealed crescentic glomerulonephritis with necrotizing vasculitis, which was associated with a high serum titer of MPO-ANCA, leading to a diagnosis of MPA. Remission-induction treatment with glucocorticoids and rituximab was initiated, which improved the patient's general condition and renal failure. His blood pressure was elevated and was controlled by amlodipine treatment. Two months after discharge, he visited the emergency department because of chest pain. A diagnosis of acute cardiovascular syndrome was suggested; however, his cardiac artery was not stenotic. The patient's blood pressure was high despite antihypertensive therapy, and he developed posterior reversible encephalopathy syndrome (PRES). Despite intensive treatment, the patient died 3 days later. An autopsy revealed that the cause of death was hypovolemic shock due to massive intra-abdominal hemorrhage from the ruptured mesenteric artery involved in vasculitis. In cases of MPA with sudden-onset chest or abdominal pain, a ruptured intra-abdominal artery should be considered. Secondary hypertension associated with vasculitis should be carefully managed to prevent hemorrhagic complications and PRES.

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.

Mesenteric Arteriovenous Dysplasia/Vasculopathy Mimicking Crohn's Disease: A Case Report / Displasia arteriovenosa mesentérica/vasculopatía mimetizante de enfermedad de Crohn: reporte de un caso

Mesenteric arteriovenous vasculopathy (MAVD/V) is an extremely rare and poorly understood disease and its incidence is probably underestimated. It is an uncommon, non-inflammatory and non-atherosclerotic form of mesenteric vascular injury, first reported in 2016, with characteristic histopathologic evidence of fibromuscular dysplasia-like vascular changes. We present the case of a chronically ill 84-year-old female with a 5 year history of recurrent small bowel obstruction, who underwent segmental resection of the small bowel. Intraoperative examination showed bowel stricture with fibrosis, intraluminal pill fragments and creeping mesenteric adipose tissue clinically compatible with Crohn's disease. Histological examination showed acute and chronic mucosal injury characterized by crypt distortion, ulcerations with granulation tissue, pseudo-pyloric metaplasia, areas of fibrosis and serosal adhesions. Multiple blood vessels (including both veins and arteries) demonstrated wall hyalinization, elastic degeneration and non-atherosclerotic luminal occlusion. The pattern of the mucosal injury is, in this case, potentially a consequence of acute and chronic ischemic processes secondary to mesenteric arteriovenous vasculopathy

La vasculopatía arteriovenosa mesentérica (MAVD/V) es una enfermedad extremadamente rara y poco conocida, con una incidencia probablemente subestimada. Se trata de una forma infrecuente, no inflamatoria y no aterosclerótica de lesión vascular mesentérica, reportada por primera vez en 2016, con evidencia histopatológica característica de cambios vasculares de tipo displasia fibromuscular. Presentamos el caso de una paciente crónica de 84 años de edad, con historia de cinco años de obstrucción recurrente de intestino delgado a quien se le practicó resección segmental del mismo. El examen intraoperatorio reveló estenosis intestinal con fibrosis, fragmentos intraluminales de píldoras, y tejido adiposo mesentérico serpiginoso clínicamente compatible con enfermedad de Crohn. El examen histológico reveló lesión mucosa aguda y crónica, evidenciada por distorsión de la cripta, ulceraciones con tejido granuloso, metaplasia pseudopilórica, áreas de fibrosis y adherencias serosas. Los múltiples vasos sanguíneos (incluyendo venas y arterias) reflejaron hialinización de la pared, degeneración elástica y oclusión luminal no aterosclerótica. El patrón de la lesión mucosa es, en este caso, una consecuencia potencial de un proceso isquémico crónico secundario a vasculopatía arteriovenosa mesentérica

Evaluation of mesenteric artery disease in patients with severe aortic valve stenosis.

The aim of this study is to evaluate the mesenteric artery stenosis (MAS) in routinely performed CT angiography (CTA) of patients with severe aortic stenosis (AS) planned for transcatheter aortic valve implantation (TAVI) before the procedure. Patients with AS (AS group) who routinely underwent CTA before the TAVI procedure due to severe AS and patients who had CTA for other indications (control group) were retrospectively and sequentially scanned. The demographic characteristics of the patients in both groups were similar. Calcification and stenosis in the mesenteric arteries were recorded according to the localization of celiac truncus, superior mesenteric artery (SMA) and inferior mesenteric artery (IMA). Class 0-3 classification was used for calcification score. Stenoses with a stenosis degree ≥50% were considered as significant. A total of 184 patients, 73 patients with severe AS and 111 control groups, were included in the study. SMA and IMA calcification scores of patients with AS were significantly higher than the control group (p=0.035 for SMA and p=0.020 for IMA). In addition, the rate of patients with significant MAS in at least 1 artery (45.2% vs 22.5%, p=0.001) and the rate of patients with significant stenosis in multiple arteries were also significantly higher in the AS group (8.2% vs 1.8%, p=0.037). According to the study results, patients with AS are at a higher risk for MAS. Chronic mesenteric ischemia should be kept in mind in patients with AS who have symptoms such as non-specific abdominal pain and weight loss.

Celiac trunk segmental arterial mediolysis: a rare cause of arteriopathy

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Single-cell RNA sequencing reveals cell type- and artery type-specific vascular remodelling in male spontaneously hypertensive rats.

AIMS: Hypertension is a major risk factor for cardiovascular diseases. However, vascular remodelling, a hallmark of hypertension, has not been systematically characterized yet. We described systematic vascular remodelling, especially the artery type- and cell type-specific changes, in hypertension using spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: Single-cell RNA sequencing was used to depict the cell atlas of mesenteric artery (MA) and aortic artery (AA) from SHRs. More than 20 000 cells were included in the analysis. The number of immune cells more than doubled in aortic aorta in SHRs compared to Wistar Kyoto controls, whereas an expansion of MA mesenchymal stromal cells (MSCs) was observed in SHRs. Comparison of corresponding artery types and cell types identified in integrated datasets unravels dysregulated genes specific for artery types and cell types. Intersection of dysregulated genes with curated gene sets including cytokines, growth factors, extracellular matrix (ECM), receptors, etc. revealed vascular remodelling events involving cell-cell interaction and ECM re-organization. Particularly, AA remodelling encompasses upregulated cytokine genes in smooth muscle cells, endothelial cells, and especially MSCs, whereas in MA, change of genes involving the contractile machinery and downregulation of ECM-related genes were more prominent. Macrophages and T cells within the aorta demonstrated significant dysregulation of cellular interaction with vascular cells. CONCLUSION: Our findings provide the first cell landscape of resistant and conductive arteries in hypertensive animal models. Moreover, it also offers a systematic characterization of the dysregulated gene profiles with unbiased, artery type-specific and cell type-specific manners during hypertensive vascular remodelling.

Peritoneal dialysis-related peritonitis complicated with nonocclusive mesenteric ischemia.

Peritoneal dialysis (PD)-related peritonitis is a common complication of PD. Nonocclusive mesenteric ischemia (NOMI) is a rare complication of PD-related peritonitis, has a high mortality rate, and therefore should be detected early once it occurs. We describe a case of a 70-year-old woman on PD presented with moderate abdominal pain and low blood pressure, which contributed to the early diagnosis of PD-related peritonitis complicated with NOMI. Increased white cell count of 7150/µL (neutrophil, 84%) in dialysate effluent was diagnostic of PD-related peritonitis, which was later found to be caused by Pseudomonas putida. Computed tomography with contrast performed after administering crystalloids revealed hepatic portal venous gas, pneumatosis intestinalis in the ascending colon, and normal enhancement of the bowel wall and mesenteric arteries, which suggested a reperfusion of the previously ischemic ascending colon. Colonoscopy on hospital day seventeen revealed mucosal hemorrhage and ulcers in the entire right colon and the terminal ileum while the remaining colon was normal. These findings are compatible with the consequence of NOMI. Increased peak systolic velocity of the superior mesenteric artery (SMA) implied its stenosis. Past studies show that ischemia of the colon in patients with chronic kidney disease commonly occurs in the right colon. Arteriosclerosis of the SMA due to the long history of chronic kidney disease and diabetes might have caused its vulnerability to low blood pressure. Abdominal complications including NOMI should be screened for when a patient presents with low blood pressure and strong abdominal pain. This is the first case report that shows colonoscopy images of the colonic ulcers post-NOMI and PD-related peritonitis.

Inhibition of miR-155 Attenuates Detrimental Vascular Effects of Tobacco Cigarette Smoking.

Background The role of microRNAs dysregulation in tobacco cigarette smoking-induced vascular damage still needs to be clarified. We assessed the acute effects of tobacco cigarette smoking on endothelial cell-related circulating microRNAs in healthy subjects. In addition, we investigated the potential role of microRNAs in smoking-dependent endothelial cell damage. Methods and Results A panel of endothelial-related microRNAs was quantified in healthy subjects before and after smoking 1 tobacco cigarette. Serum levels of miR-155 were found to be significantly increased shortly after smoking. We also observed a progressive and significant miR-155 accumulation in culture media of human endothelial cells after 30 minutes and up to 4 hours of cigarette smoke condensate treatment in vitro without evidence of cell death, indicating that miR-155 can be released by endothelial cells in response to smoking stress. Cigarette smoke condensate appeared to enhance oxidative stress and impair cell survival, angiogenesis, and NO metabolism in human endothelial cells. Notably, these effects were abrogated by miR-155 inhibition. We also observed that miR-155 inhibition rescued the deleterious effects of cigarette smoke condensate on endothelial-mediated vascular relaxation and oxidative stress in isolated mouse mesenteric arteries. Finally, we found that exogenous miR-155 overexpression mimics the effects of smoking stress by inducing the upregulation of inflammatory markers, impairing angiogenesis and reducing cell survival. These deleterious effects were associated with downregulation of vascular endothelial growth factor and endothelial NO synthetase. Conclusions Our results suggest that miR-155 dysregulation may contribute to the deleterious vascular effects of tobacco smoking.

Prospective Screening of Extracranial Systemic Arteriopathy in Young Adults with Moyamoya Disease.

Background RNF213 is a major susceptibility gene for moyamoya disease (MMD), characterized by chronic progressive steno-occlusion of the intracranial arteries. However, coincidental extracranial arteriopathy is sporadically described in a few cases and in children with MMD. Methods and Results This study prospectively enrolled 63 young adults (aged 20-49 years) without a known history of systemic vascular diseases who were confirmed to have definite (bilateral, n=54) or probable (unilateral, n=9) MMD, as per typical angiographic findings. Coronary and aorta computed tomography angiography was performed to characterize extracranial arteriopathy and investigate its correlation with clinical characteristics and MMD status, including the RNF213 p.Arg4810Lys variation (c.14429G>A, rs112735431). Altogether, 11 of 63 patients (17%) had significant (>50%) stenosis in the coronary (n=6), superior mesenteric (n=2), celiac (n=2), renal (n=1), and/or internal iliac artery (n=1). One patient showed both mesenteric and iliac artery stenosis. Patients with extracranial arteriopathy were more likely to have diabetes mellitus and posterior cerebral artery involvement. Moreover, a higher prevalence of extracranial arteriopathy was observed in the presence of the RNF213 p.Arg4810Lys variant (67% in homozygotes). After controlling for diabetes mellitus and posterior cerebral artery involvement, the p.Arg4810Lys variant was independently associated with extracranial arteriopathy (additive model; P=0.035; adjusted odds ratio, 4.57; 95% CI, 1.11-27.20). Conclusions Young adults with MMD may have concomitant extracranial arteriopathy in various locations. Patients with RNF213 variants, especially the p.Arg4810Lys homozygous variant, should be screened for systemic arteriopathy.

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.

Endothelial dysfunction in small arteries and early signs of atherosclerosis in ApoE knockout rats.

Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20-24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development.

Development of Alzheimer's Disease Progressively Alters Sex-Dependent KCa and Sex-Independent KIR Channel Function in Cerebrovascular Endothelium.

BACKGROUND: Development of Alzheimer's disease (AD) pathology is associated with impaired blood flow delivery of oxygen and nutrients throughout the brain. Cerebrovascular endothelium regulates vasoreactivity of blood vessel networks for optimal cerebral blood flow. OBJECTIVE: We tested the hypothesis that cerebrovascular endothelial Gq-protein-coupled receptor (GPCR; purinergic and muscarinic) and K+ channel [Ca2+-activated (KCa2.3/SK3 and KCa3.1/IK1) and inward-rectifying (KIR2.x)] function declines during progressive AD pathology. METHODS: We applied simultaneous measurements of intracellular Ca2+ ([Ca2+]i) and membrane potential (Vm) in freshly isolated endothelium from posterior cerebral arteries of 3×Tg-AD mice [young, no pathology (1- 2 mo), cognitive impairment (CI; 4- 5 mo), extracellular Aß plaques (Aß; 6- 8 mo), and Aß plaques + neurofibrillary tangles (AßT; 12- 15 mo)]. RESULTS: The coupling of ΔVm-to-Δ[Ca2+]i during AßT pathology was lowest for both sexes but, overall, ATP-induced purinergic receptor function was stable throughout AD pathology. SKCa/IKCa channel function itself was enhanced by ∼20% during AD (Aß+ AßT) versus pre-AD (Young + CI) in males while steady in females. Accordingly, hyperpolarization-induced [Ca2+]i increases following SKCa/IKCa channel activation and Δ[Ca2+]i-to-ΔVm coupling was enhanced by ≥two-fold during AD pathology in males but not females. Further, KIR channel function decreased by ∼50% during AD conditions versus young regardless of sex. Finally, other than a ∼40% increase in females versus males during Aß pathology, [Ca2+]i responses to the mitochondrial uncoupler FCCP were similar among AD versus pre-AD conditions. CONCLUSION: Altogether, AD pathology represents a condition of altered KCa and KIR channel function in cerebrovascular endothelium in a sex-dependent and sex-independent manner respectively.

Ketogenic diet aggravates hypertension via NF-κB-mediated endothelial dysfunction in spontaneously hypertensive rats.

AIMS: Ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome. However, the effects of KD on hypertension have not been well investigated. The present study aimed to investigate the effects and underling mechanisms of KD on hypertension in spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS: SHRs were subjected to normal diet or KD for 4 weeks, starting at the age of 10 weeks. Then, the blood pressure and vascular function were assessed. Next, the eNOS expression, inflammatory factors and relative signaling pathway were examined. Human umbilical vein endothelial cells were used to investigate the underlying mechanism account for the effect of ketone on inflammation and eNOS expression. KEY FINDINGS: Compared with the normal diet, KD was indicated to aggravate hypertension and impaire endothelium-dependent relaxation in mesenteric arteries of SHRs. eNOS and CD31 expression in mesenteric arteries were also significantly suppressed by KD. In addition, KD markedly increased the activation of NF-κB pathway and the expression of IL1-ß and TNF-α. In vitro, results showed that inhibition of NF-κB could rescue the adverse effects of ketone body and TGF-ß on eNOS expression and inflammation response. SIGNIFICANCE: Our study indicated that KD impaired endothelium-dependent relaxation in mesenteric arteries and aggravated the development of hypertension in SHRs, suggesting that it should be more cautious to apply KD into clinical application in hypertensive individuals.