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Inflammatory Bowel Diseases (IBDs) are associated with aberrant immune function, widespread inflammation, and altered intestinal blood flow. Perivascular adipose tissue (PVAT) surrounding the mesenteric vasculature can modulate vascular function and control the local immune cell population, but its structure and function have never been investigated in IBD. We used an IL10−/− mouse model of colitis that shares features with human IBD to test the hypothesis that IBD is associated with (1) impaired ability of PVAT to dilate mesenteric arteries and (2) changes in PVAT resident adipocyte and immune cell populations. Pressure myography and electrical field stimulation of isolated mesenteric arteries show that PVAT not only loses its anti-contractile effect but becomes pro-contractile in IBD. Quantitative immunohistochemistry and confocal imaging studies found significant adipocyte hyperplasia and increased PVAT leukocytes, particularly macrophages, in IBD. PCR arrays suggest that these changes occur alongside the altered cytokine and chemokine gene expression associated with altered NF-κB signaling. Collectively, these results show that the accumulation of macrophages in PVAT during IBD pathogenesis may lead to local inflammation, which ultimately contributes to increased arterial constriction and decreased intestinal blood flow with IBD. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical Abstract

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. Highlights: Prenatal hypoxia increases thromboxane-mediated vasoconstrictor responses in both coronary and mesenteric arteries from the adult female and male offspring. This was more pronounced in females, and was prevented by maternal placental antioxidant treatment in pregnancy. The mechanisms for the increased thromboxane-mediated vasoconstrictor responses by prenatal hypoxia exposure were sex-specific, where females had reduced nitric oxide modulation of vasoconstriction, while males had increased thromboxane receptor expression. There are sex-specific differences on how prenatal hypoxia impairs vascular function in the adult offspring. Placenta-targeted therapies in pregnancy should be considered to improve cardiovascular outcomes in the offspring later life but should take the sex of the fetus into consideration. Plain language summary: 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening. METHODS: Mesenteric arteries were isolated from old (20–23 months) littermate Mfap4 +/+ and Mfap4 −/− mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall. Ten-week-old littermate Mfap4 +/+ and Mfap4 −/− mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure-myography. Collagen contents were assessed by Western blotting. RESULTS: MFAP4-deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive Mfap4 +/+ mice relative to Mfap4 −/− mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated Mfap4 −/− mouse mesenteric arteries in ex vivo myography recordings. CONCLUSIONS: MFAP4-deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension. [ABSTRACT FROM AUTHOR]

Background: Superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) are vital vascular structures supplying the majority of the intestinal tract. Despite their clinical significance, comprehensive morphometric studies combining traditional cadaveric dissection with modern imaging techniques are scarce in literature. This study aimed to provide a detailed morphometric analysis of the SMA and IMA using both cadaveric dissection and multi-detector computed tomography (MDCT) angiography. Methods: The study utilized a dual approach, combining cadaveric dissection (30 formalin-fixed cadavers) and MDCT angiography (images from 50 patients). Measurements including stem lengths, diameters at origin, and distances from the aortic bifurcation were taken, along with assessment of vertebral levels of origin and branching patterns. Data from both components were analyzed using descriptive statistics. Results: Key findings for SMA include: Mean stem length: 3.19 ± 0.72 cm (cadaveric) vs. 2.53 ± 0.53 cm (MDCT); Mean diameter at origin: 0.93 ± 0.22 cm (cadaveric) vs. 0.57 ± 0.10 cm (MDCT); Most common vertebral level of origin: Upper border of L1 (78 % of cases); Branching pattern variations observed in 23.3 % of cadaveric specimens, which included the origin of the inferior pancreaticoduodenal artery from the first jejunal artery, a common trunk for right colic and ileocolic arteries, and absence of middle colic artery. For IMA: Mean stem length: 3.61 ± 1.29 cm (cadaveric) vs. 3.41 ± 0.69 cm (MDCT); Mean diameter at origin: 0.50 ± 0.11 cm (cadaveric) vs. 0.26 ± 0.05 cm (MDCT); Most common vertebral level of origin: Upper border of L3 (40 % of cases). No variations observed in branching pattern. Conclusions: The detailed measurements, frequency of variations, and comparison between traditional and modern assessment techniques offer a nuanced understanding of mesenteric vascular anatomy. This study bridges the gap between classical anatomical knowledge and contemporary imaging capabilities, potentially improving surgical planning, interventional procedures, and radiological interpretation.

Endovascular revascularization of visceral arteries is an important cornerstone of an interdisciplinary treatment concept for both acute and chronic forms of mesenteric ischemia. The advantages lie in the minimally invasive procedure and the speed of restoration of perfusion. This article provides an overview of the indications, techniques and current state of the clinical literature with respect to endovascular revascularization. [ABSTRACT FROM AUTHOR]

Wilkie's syndrome is an unusual cause of upper intestinal obstruction due to mechanical compression of the superior mesenteric artery (SMA) to the duodenum, with nonspecific symptoms, whose diagnosis is confirmed by angiotomography. Initially, the treatment is conservative to regain weight and restore mesenteric adipose tissue, associated with postural changes of the patient. If this fails, surgical treatment is indicated, being laparoscopic duodenojejunostomy described as the gold standard. Robotics' assistance is feasible and safe to carry out the procedure. We present the case of a 21-year-old male patient who comes with stabbing abdominal pain and persistent postprandial vomiting that has caused weight loss of 11 kilograms in the last 2 years without apparent cause, associated with gastroesophageal reflux. During the procedure, we evidenced open diaphragmatic pillars and duodenal compression due to SMA, and robotic-assisted laparoscopic hyatoplasty + Nissen fundoplication + duodenojejunostomy were performed without complications, with excellent post-surgical results. [ABSTRACT FROM AUTHOR]

Tree and shrub barks have been used as folk medicine by numerous cultures across the globe for millennia, for a variety of indications, including as vasorelaxants and antispasmodics. Here, using electrophysiology and myography, we discovered that the KCNQ5 voltage-gated potassium channel mediates vascular smooth muscle relaxant effects of barks used in Native American folk medicine. Bark extracts (1%) from Birch, Cramp Bark, Slippery Elm, White Oak, Red Willow, White Willow, and Wild Cherry each strongly activated KCNQ5 expressed in Xenopus oocytes. Testing of a subset including both the most and the least efficacious extracts revealed that Red Willow, White Willow, and White Oak KCNQ-dependently relaxed rat mesenteric arteries; in contrast, Black Haw bark neither activated KCNQ5 nor induced vasorelaxation. Two compounds common to the active barks (gallic acid and tannic acid) had similarly potent and efficacious effects on both KCNQ5 activation and vascular relaxation, and this together with KCNQ5 modulation by other tannins provides a molecular basis for smooth muscle relaxation effects of Native American folk medicine bark extracts.

Inflammatory Bowel Diseases (IBDs) are associated with aberrant immune function, widespread inflammation, and altered intestinal blood flow. Perivascular adipose tissue (PVAT) surrounding the mesenteric vasculature can modulate vascular function and control the local immune cell population, but its structure and function have never been investigated in IBD. We used an IL10−/− mouse model of colitis that shares features with human IBD to test the hypothesis that IBD is associated with (1) impaired ability of PVAT to dilate mesenteric arteries and (2) changes in PVAT resident adipocyte and immune cell populations. Pressure myography and electrical field stimulation of isolated mesenteric arteries show that PVAT not only loses its anti-contractile effect but becomes pro-contractile in IBD. Quantitative immunohistochemistry and confocal imaging studies found significant adipocyte hyperplasia and increased PVAT leukocytes, particularly macrophages, in IBD. PCR arrays suggest that these changes occur alongside the altered cytokine and chemokine gene expression associated with altered NF-κB signaling. Collectively, these results show that the accumulation of macrophages in PVAT during IBD pathogenesis may lead to local inflammation, which ultimately contributes to increased arterial constriction and decreased intestinal blood flow with IBD.

Myoendothelial feedback (MEF), the endothelium-dependent vasodilation following sympathetic vasoconstriction (mediated by smooth muscle to endothelium gap junction communication), has been well studied in resistance arteries of males, but not females. We hypothesized that MEF responses would be similar between the sexes, but different in the relative contribution of the underlying nitric oxide and hyperpolarization mechanisms, given that these mechanisms differ between the sexes in agonistinduced endothelium-dependent dilation. We measured MEF responses (diameter changes) of male and female first- to secondorder mouse mesenteric arteries to phenylephrine (10 lM) over 30 min using isolated pressure myography ± blinded inhibition of nitric oxide synthase (NOS) using Nx-nitro-L-arginine methyl ester (L-NAME; 0.1-1.0 mM), hyperpolarization using 35 mM KCl, or transient receptor potential vanilloid 4 (TRPV4) channels using GSK219 (0.1-1.0 lM) or RN-1734 (30 lM). MEF was similar [%dilation (means ± SE): males = 26.7 ± 2.0 and females = 26.1 ± 1.9 at 15 min] and significantly inhibited by L-NAME (1.0 mM) at 15 min [%dilation (means ± SE): males = 8.2 ± 3.3, P < 0.01; females = 6.8 ± 1.9, P < 0.001] and over time (P < 0.01) in both sexes. LNAME (0.1 mM) þ 35 mM KCl nearly eliminated MEF in both sexes (P < 0.001-0.0001). Activation of TRPV4 with GSK101 (0.1-10 lM) induced similar dilation between the sexes. Inhibition of TRPV4, which is reportedly involved in the hyperpolarization mechanism, did not inhibit MEF in either sex. Similar expression of eNOS was found between the sexes with Western blot. Thus, MEF is prominent and similar in murine first- and second-order mesenteric resistance arteries of both sexes, and reliant primarily on NOS and secondarily on hyperpolarization, but not TRPV4. [ABSTRACT FROM AUTHOR]

Cigarette smoke, including secondhand smoke (SHS), has significant detrimental vascular effects, but its effects on myogenic tone of small resistance arteries and the underlying mechanisms are understudied. Although it is apparent that SHS contributes to endothelial dysfunction, much less is known about how this toxicant alters arterial myocyte contraction, leading to alterations in myogenic tone. The study's goal is to determine the effects of SHS on mesenteric arterial myocyte contractility and excitability. C57BL/6J male mice were randomly assigned to either filtered air (FA) or SHS (6 h/d, 5 d/wk) exposed groups for a 4, 8, or 12-weeks period. Third and fourth-order mesenteric arteries and arterial myocytes were acutely isolated and evaluated with pressure myography and patch clamp electrophysiology, respectively. Myogenic tone was found to be elevated in mesenteric arteries from mice exposed to SHS for 12 wk but not for 4 or 8 wk. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 wk of SHS exposure. Moreover, 12 wk SHS exposed arterial myocytes have reduced total potassium channel current density, which correlates with a depolarized membrane potential (Vm). These results suggest that SHS exposure induces alterations in key ionic conductances that modulate arterial myocyte contractility and myogenic tone. Thus, chronic exposure to an environmentally relevant concentration of SHS impairs mesenteric arterial myocyte electrophysiology and myogenic tone, which may contribute to increased blood pressure and risks of developing vascular complications due to passive exposure to cigarette smoke.

Abstract Background Chronic mesenteric ischemia (CMI) is a debilitating disease with a heavy burden on quality of life. Stenting of the superior mesenteric artery (SMA) is the first option for treatment, but there is a lack of consensus defining precise indications for open revascularization (OR). Objectives To describe a series of 4 patients with CMI treated with OR and to present an algorithm for the management of this condition. Methods Three patients presented with typical intestinal angina and weight loss. One patient was subjected to prophylactic revascularization during open abdominal aortic aneurysm repair. Surgical techniques included: 1) Bypass from the infrarenal aorta to the SMA; 2) Bypass from an aorto-bifemoral polyester graft to the SMA; 3) Bypass from the right iliac artery to the SMA; 4) Bypass from the right graft limb of an aorto-biiliac polyester graft to the median colic artery at Riolan’s arcade. PTFE was used in all surgeries. All grafts were placed in a retrograde configuration, tunneled under the left renal vein, making a smooth C-loop. A treatment algorithm was constructed based on the institution’s experience and a review of recent literature. Results All patients demonstrated resolution of symptoms and recovery of body weight. All grafts are patent after mean follow-up of two years. Conclusions Open revascularization using the C-loop configuration is a valuable technique for CMI and may be considered in selected cases. The algorithm constructed may help decision planning in other quaternary centers.

Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann–Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2–3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 300 μM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca2+ channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties. [ABSTRACT FROM AUTHOR]

Background/aimsTea, produced from the evergreen Camellia sinensis, has reported therapeutic properties against multiple pathologies, including hypertension. Although some studies validate the health benefits of tea, few have investigated the molecular mechanisms of action. The KCNQ5 voltage-gated potassium channel contributes to vascular smooth muscle tone and neuronal M-current regulation.MethodsWe applied electrophysiology, myography, mass spectrometry and in silico docking to determine effects and their underlying molecular mechanisms of tea and its components on KCNQ channels and arterial tone.ResultsA 1% green tea extract (GTE) hyperpolarized cells by augmenting KCNQ5 activity >20-fold at resting potential; similar effects of black tea were inhibited by milk. In contrast, GTE had lesser effects on KCNQ2/Q3 and inhibited KCNQ1/E1. Tea polyphenols epicatechin gallate (ECG) and epigallocatechin-3-gallate (EGCG), but not epicatechin or epigallocatechin, isoform-selectively hyperpolarized KCNQ5 activation voltage dependence. In silico docking and mutagenesis revealed that activation by ECG requires KCNQ5-R212, at the voltage sensor foot. Strikingly, ECG and EGCG but not epicatechin KCNQ-dependently relaxed rat mesenteric arteries.ConclusionKCNQ5 activation contributes to vasodilation by tea; ECG and EGCG are candidates for future anti-hypertensive drug development.

Aim. To evaluate the clinical and endoscopic features of diseases of the upper gastrointestinal tract (GIT) in patients with atherosclerosis of the mesenteric arteries (MA). Materials and methods. The study included 48 patients with atherosclerosis of MA and 43 patients without atherosclerosis of MA, who were hospitalized in the department of vascular surgery of the Chelyabinsk Regional Clinical Hospital in the period from 2019 to 2021. All patients underwent multispiral computed tomoangiography of the visceral and lower limb arteries, esophagogastroduodenoscopy. Results. Assessment of lesions of the upper gastrointestinal tract revealed a higher incidence of erosive and ulcerative gastroduodenopathies among patients with atherosclerosis of MA (60.4%), compared with patients without atherosclerosis MA (39.5%); p=0.047. Signs of severe atrophy according to the data of histological examination were statistically significantly more frequent among patients with atherosclerosis of MA (29.2 and 11.6%; p=0.031). According to the results of logistic regression, the following predictors of erosions and ulcers of the upper gastrointestinal tract were revealed: the severity of stenosis of the superior mesenteric artery (SMA) is more than 35%, the body mass index (BMI) is less than 25.9 and the total score on the HADS scale is more than 6.5 points for depression (p=0.008). Conclusion. Erosive-ulcerative gastroduodenopathies and atrophy of the gastric mucosa are significantly more common in the group of patients with MA atherosclerosis. The main risk factors for erosions and ulcers of the upper gastrointestinal tract in patients with MA atherosclerosis are: the severity of SMA stenosis is more than 35%, a decrease in BMI is less than 25.9 and an increase in the HADS score is more than 6.5 points.

Objective: To identify the vascular distribution patterns of the splenic flexure of the colon (AEC) in the Chilean population for comparison with the oriental literature (Fukuoka). Methods: Descriptive, cross-sectional study. The irrigation of the AEC of images with the Urotac protocol performed at the INDISA Clinic between 2020 and 2021 (n = 127) was characterized, classifying them into 6 types described by Fukuoka. Demographic characteristics and comorbidities were evaluated. Variables were analyzed using descriptive statistics and significance using the Chi2 test. Results: There are differences in the types of irrigation of the AEC between the local series and Fukuoka, irrigation type 3 was the one that presented the greatest variation (p < 0.05). Type 1 is the most frequent (34.7%), with no cases of Type 4. No difference was identified between the different types of irrigation in relation to demographic variables and comorbidities. Discussion: When comparing our series with the eastern one, a similar frequency was found in types 1 and 6, higher in types 3 and 5, and types 2 and 4 with less representation. A greater contribution was identified in the irrigation of the AEC by the left colic artery (ICA) in the population studied (64.6%). Conclusion: Our population has a greater participation of ICA in AEC irrigation than Orientals (64.6% vs 49.6%), the most frequent types are 1, 3 and 6, Type 1 is the most frequent form of irrigation, similar to Fukuoka (34.7% vs 39.7%), Type 3 is more represented in our population than in the eastern one (29.9% vs 9.9%). [ABSTRACT FROM AUTHOR]

Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. However, there is insufficient evidence to establish the timeline of the vascular dysfunction in diabetes, specifically in relation to sex. Here, we determined whether mesenteric arterial function is altered in UC Davis Type-2 Diabetes Mellitus (UCD-T2DM) rats and if this occurs as early as the pre-diabetic stage of the disease. Specifically, we investigated whether vascular dysfunction differs between pre-diabetic or diabetic status and if this varies by sex. We measured the responses to endothelium-dependent and -independent vasorelaxant as well as vasoconstrictor agents and explored the potential mechanisms involved in sex-specific development of arterial dysfunction in UCD-T2DM rats. In addition, indices of insulin sensitivity were assessed. We report the reduced insulin sensitivity in pre-diabetic males and diabetic females. Vascular relaxation to acetylcholine was impaired to a greater extent in mesenteric artery from males in the pre-diabetic stage than in their female counterparts. In contrast, the arteries from females with diabetes exhibited a greater impairment to acetylcholine compared with diabetic males. Additionally, the sensitivity of mesenteric artery to contractile agents in females, but not in males, after the onset of diabetes was increased. Our data suggest that the reduced insulin sensitivity through AKT may predispose vessels to injury in the pre-diabetic stage in males. On the other hand, reduced insulin sensitivity as well as enhanced responsiveness to contractile agents may predispose arteries to injury in the diabetic stage in females.

ObjectiveIntravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown. Approach and Results: Here, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation.ConclusionsDirect and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mechanism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by concurrent inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 (by 1 μM DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 μM linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa by 1 μM apamin, IKCa 10 μM TRAM-34, and BKCa by 10 μM paxilline, respectively), ATP-sensitive (KATP) channels (by 10 μM glibenclamide), or SERCA pump (by 0.1 μM thapsigargin). Inhibition of SGLTs (by 1 μM phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that canagliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure.

Spontaneous isolated mesenteric arterial dissection (SIMAD) is an uncommon subset of non-traumatic dissection of the mesenteric arteries without concurrent aortic dissection. Due to the widespread use of computer tomography angiography, SIMAD cases have been increasingly reported in the past 20 years. Common risk factors associated with SIMAD include male gender, age 50–60 years, hypertension and smoking. This review summarises the diagnostic pathway and management of SIMAD based on contemporary literature and proposes a treatment algorithm for SIMAD. The presentation of SIMAD can be divided into symptomatic and asymptomatic cases. Symptomatic patients should be carefully assessed to detect the development of complications, particularly bowel ischemia or vessel rupture. Although these complications are rare, they necessitate urgent surgical management. The vast majority of symptomatic SIMAD cases are uncomplicated and can be managed safely with conservative treatment that includes antihypertensive therapy, bowel rest, with or without antithrombotic therapy. For asymptomatic SIMAD cases, expectant management with outpatient surveillance imaging appears to be a safe strategy. [ABSTRACT FROM AUTHOR]

Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na+ (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications. [ABSTRACT FROM AUTHOR]

Acute mesenteric ischemia (AMI) is an uncommon yet highly lethal cause of acute abdomen in the emergency setting. Computed tomography (CT) imaging, in particular a biphasic protocol consisting of angiographic and venous phase scans, is widely used to corroborate non-specific clinical findings when suspicions of AMI are high. Techniques such as low kilovoltage peak scanning, dual energy acquisition, or a combined arterial/enteric phase can improve iodine conspicuity and evaluation of bowel enhancement. Biphasic CT with CT angiography is mandatory to directly assess for the 3 primary etiologies of AMI—arterial, venous, and non-occlusive mesenteric ischemia (NOMI), and the CT angiographic findings may be the first visible in the disease. In addition, numerous non-vascular CT findings have also been reported. Bowel wall thickening, mesenteric stranding, and ascites are common but non-specific findings that correlate poorly with disease severity. Pneumatosis intestinalis and portomesenteric venous gas, while not pathognomonic for ischemia, are highly specific in cases of high clinical suspicion. Bowel wall hypoenhancement is an early and specific sign but requires a protocol optimizing iodine conspicuity to confidently identify. Finally, intraperitoneal free air and solid organ infarcts are also highly specific ancillary findings in AMI. AMI occurs as a complication in 10% of small bowel obstruction (SBO) patients, and understanding imaging findings of ischemia in the context of SBO is necessary to aid in treatment planning and reduce over- and under-diagnosis of strangulation. Familiarity with the imaging features of ischemia by radiologists is vital to establish an early diagnosis before irreversible necrosis occurs. [ABSTRACT FROM AUTHOR]

Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann–Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2–3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 300 μM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca2+ channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties.

Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.

To elucidate molecular mechanisms responsible for the sexually dimorphic phenotype of soluble epoxide hydrolase (sEH) expression, we tested the hypothesis that female-specific down-regulation of sEH expression is driven by estrogen-dependent methylation of the Ephx2 gene. Mesenteric arteries isolated from male, female, ovariectomized female (OV), and OV with estrogen replacement (OVE) mice, as well as the human cell line (HEK293T) were used. Methylation-specific PCR and bisulfite genomic sequencing analysis indicate significant increases in DNA/CG methylation in vessels of female and OVE compared with those of male and OV mice. The same increase in CG methylation was also observed in male vessels incubated with a physiological concentration of 17β-estradiol (17β-E2) for 48 hours. All vessels that displayed increases in CG methylation were concomitantly associated with decreases in their Ephx2 mRNA and protein, suggesting a methylation-induced gene silencing. Transient transfection assays indicate that the activity of Ephx2 promoter-coding luciferase was significantly attenuated in HEK293T cells treated with 17β-E2, which was prevented by additional treatment with an estrogen receptor antagonist (ICI). ChIP analysis indicates significantly reduced binding activities of transcription factors (including SP1, AP-1, and NF-κB with their binding elements located in the Ephx2 promoter) in vessels of female mice and human cells treated with 17β-E2, responses that were prevented by ICI and Decitabine (DNA methyltransferase inhibitor), respectively. In conclusion, estrogen/estrogen receptor-dependent methylation of the promoter of Ephx2 gene silences sEH expression, which is involved in specific transcription factor-directed regulatory pathways.

Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that 1) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness, 2) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase, and 3) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Lastly, we demonstrated that in vivo treatment of db/db mice with adropin for 4 wk reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelium-derived NO, and thus support the notion that “hypoadropinemia” should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D. NEW & NOTEWORTHY Arterial stiffening, a characteristic feature of obesity and type 2 diabetes (T2D), contributes to the development and progression of cardiovascular diseases. Herein we establish that adropin is decreased in obese and T2D models and furthermore provide evidence that reduced adropin may directly contribute to arterial stiffening. Collectively, findings from this work support the notion that “hypoadropinemia” should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer - (R)-PZQ - which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.

Background: The voltage-gated potassium channel (Kv)7.4 and Kv7.5 channels contribute to the β-adrenoceptor-mediated vasodilatation. In arteries from hypertensive rodents, the Kv7.4 channel is downregulated and function attenuated, which contributes to the reduced β-adrenoceptor-mediated vasodilatation observed in these arteries. Recently, we showed that disruption of the microtubule network, with colchicine, or inhibition of the microtubule motor protein, dynein, with ciliobrevin D, enhanced the membrane abundance and function of Kv7.4 channels in rat mesenteric arteries. This study aimed to determine whether these pharmacological compounds can improve Kv7.4 function in third-order mesenteric arteries from the spontaneously hypertensive rat, thereby restoring the β-adrenoceptor-mediated vasodilatation.Methods: Wire and intravital myography was performed on normotensive and hypertensive male rat mesenteric arteries and immunostaining was performed on isolated smooth muscle cells from the same arteries.Results: Using wire and intravital microscopy, we show that ciliobrevin D enhanced the β-adrenoceptor-mediated vasodilatation by isoprenaline. This effect was inhibited partially by the Kv7 channel blocker linopirdine and was dependent on an increased functional contribution of the β2-adrenoceptor to the isoprenaline-mediated relaxation. In mesenteric arteries from the spontaneously hypertensive rat, ciliobrevin D and colchicine both improved the isoprenaline-mediated vasorelaxation and relaxation to the Kv7.2 -7.5 activator, ML213. Immunostaining confirmed ciliobrevin D enhanced the membrane abundance of Kv7.4. As well as an increase in the function of Kv7.4, the functional changes were associated with an increase in the contribution of β2-adrenoceptor following isoprenaline treatment. Immunostaining experiments showed ciliobrevin D prevented isoprenaline-mediated internalizationof the β2-adrenoceptor.Conclusions: Overall, these data show that colchicine and ciliobrevin D can induce a β2-adrenoceptor-mediated vasodilatation in arteries from the spontaneously hypertensive rat as well as reinstating Kv7.4 channel function. [ABSTRACT FROM AUTHOR]

Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na+ (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications.

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that, in addition to glucose reduction, lowers systemic blood pressure. Here, we investigated if dapagliflozin could directly relax small mesenteric arteries that control peripheral vascular resistance and blood pressure, and the underlying molecular mechanism. We used pressurized arterial myography, pharmacological inhibition and Western blotting to investigate the direct effect of dapagliflozin on the contractility of freshly isolated, resistance-size rat mesenteric arteries. Our pressure myography data unveiled that dapagliflozin relaxed small mesenteric arteries in a concentration-dependent manner. Non-selective inhibition of KV channels and selective inhibition of smooth muscle cell voltage-gated K+ channels KV7 attenuated dapagliflozin-induced vasorelaxation. Inhibition of other major KV isoforms such as KV1.3, KV1.5 channels as well as large-conductance Ca2+-activated K+ (BKCa) channels, ATP-sensitive (KATP) channels did not abolish vasodilation. Dapagliflozin-evoked vasodilation remained unaltered by pharmacological inhibition of endothelium-derived nitric oxide (NO) signaling, prostacyclin (PGI2), as well as by endothelium denudation. Our Western blotting data revealed that SGLT2 protein is expressed in rat mesenteric arteries. However, non-selective inhibition of SGLTs did not induce vasodilation, demonstrating that the vasodilatory action is independent of SGLT2 inhibition. Overall, our data suggests that dapagliflozin directly and selectively stimulates arterial smooth muscle cells KV7 channels, leading to vasodilation in resistance-size mesenteric arteries. These findings are significant as it uncovers for the first time a direct vasodilatory action of dapagliflozin in resistance mesenteric arteries, which may lower systemic blood pressure.

BackgroundIntestinal circulation and mesenteric arterial (MA) reactivity may play a role in preparing the fetus for enteral nutrition. We hypothesized that MA vasoreactivity changes with gestation and vasodilator pathways predominate in the postnatal period.MethodsSmall distal MA rings (0.5-mm diameter) were isolated from fetal (116-d, 128-d, 134-d, and 141-d gestation, term ~ 147 d) and postnatal lambs. Vasoreactivity was evaluated using vasoconstrictors (norepinephrine (NE) after pretreatment with propranolol and endothelin-1(ET-1)) and vasodilators (NO donors A23187 and s-nitrosopenicillamine (SNAP)). Protein and mRNA assays for receptors and enzymes (endothelin receptor A, alpha-adrenergic receptor 1A (ADRA1A), endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase5 (PDE5)) were performed in mesenteric arteries.ResultsMA constriction to NE and ET-1 peaked at 134 d. Relaxation to A23187 and SNAP was maximal after birth. Basal eNOS activity was low at 134 d. ADRA1A mRNA and protein increased significantly at 134 d and decreased postnatally. sGC and PDE5 protein increased from 134 to 141 d.ConclusionMesenteric vasoconstriction predominates in late-preterm gestation (134 d; the postconceptional age with the highest incidence of necrotizing enterocolitis (NEC)) followed by a conversion to vasodilatory influences near the time of full-term birth. Perturbations in this ontogenic mechanism, including preterm birth, may be a risk factor for NEC.

Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) α-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established roles in the heart (Kv7.1) and the brain (Kv7.2-5). In vivo, Kv7 α-subunits are often regulated by KCNE subfamily ancillary (β) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to α-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first known molecular mechanism for sex-specificity of this modulation that has important implications for vascular reactivity and may underlie sex-specific susceptibility to cardiovascular diseases.

Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) α-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established roles in the heart (Kv7.1) and the brain (Kv7.2-5). In vivo, Kv7 α-subunits are often regulated by KCNE subfamily ancillary (β) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to α-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first known molecular mechanism for sex-specificity of this modulation that has important implications for vascular reactivity and may underlie sex-specific susceptibility to cardiovascular diseases.

Background: Abdominal apoplexy is one of the rare causes of non-traumatic intra-abdominal bleeding. This condition is usually seen in male patients in their 50s with history of hypertension. As soon as abdominal apoplexy is suspected, immediate resuscitation should be performed followed by emergent surgery. The patientchr('39')s outcome depends entirely on the clinical condition and the time interval between diagnosis and treatment. Case Presentation: Herein we present a 63-year-old man with idiopathic spontaneous intraperitoneal hemorrhage (ISIH) caused by spontaneous rupture of non-aneurysmal inferior pancreaticoduodenalartery (IPDA). Conclusion: In this report, a case of abdominal apoplexy has been presented caused by spontaneous rupture of non-aneurysmal inferior pancreaticoduodenalartery (IPDA) in a patient without any significant past medical history.

Exercise training (ET) is well established to induce vascular adaptations on the metabolically active muscles. These adaptations include increased function of vascular potassium channels and enhanced endothelium-dependent relaxations. However, the available data on the effect of ET on vasculatures that normally constrict during exercise, such as mesenteric arteries (MA), are scarce and not conclusive. Therefore, this study hypothesized that 10 weeks of moderate-intensity ET would result in adaptations towards more vasoconstriction or/and less vasodilatation of MA. Young Fischer 344 rats were randomly assigned to a sedentary group (SED; n=24) or exercise training group (EXE; n=28). The EXE rats underwent a progressive treadmill ET program for 10 weeks. Isometric tensions of small (SED; 252.9±29.5 μm, EXE; 248.6±34.4 μm) and large (SED; 397.7±85.3 μm, EXE; 414.0±86.95 μm) MA were recorded in response to cumulative phenylephrine concentrations (PE; 0-30 μM) in the presence and absence of the BKCa channel blocker, Iberiotoxin (100 nM). In another set of experiments, tensions in response to cumulative concentration-response curves of acetylcholine (ACh) or sodium nitroprusside (SNP) were obtained, and pEC50s were compared. Immunoblotting was performed to measure protein expression levels of the BKCa channel subunits and eNOS. ET did not alter the basal tension of small and large MA but significantly increased their responses to PE, and reduced the effect of BKCa channels in opposing the contractile responses to PE without changes in the protein expression level of BKCa subunits. ET also elicited a sizedependent functional adaptations that involved reduced endothelium-independent and endothelium-dependent relaxations. In large MA the sensitivity to SNP was decreased more than in small MA suggesting impaired nitric oxide (NO)-dependent mechanisms within the vascular smooth muscle cells of ET group. Whereas the shift in pEC50 of ACh-induced relaxation of small MA would suggest more effect on the production of NO within the endothelium, which is not changed in large MA of ET group. However, the eNOS protein expression level was not significantly changed between the ET and SED groups. In conclusion, our results indicate an increase in contraction and reduced relaxation of MA after 10 weeks of ET, an adaptation that may help shunt blood flow to metabolically active tissues during acute exercise. [ABSTRACT FROM AUTHOR]

Soluble guanylyl cyclase (sGC, also called GC1) is the main receptor for nitric oxide (NO) that catalyzes the production of the second messenger molecule, 3′5′ cyclic guanosine monophosphate (cGMP) leading to vasorelaxation, and inhibition of leukocyte recruitment and platelet aggregation. Enhancing cGMP levels, through sGC agonism or inhibition of cGMP breakdown via phosphodiesterase inhibition, has yielded FDA approval for several cGMP modifier therapies for treatment of cardiovascular and pulmonary diseases. While basic research continues to improve our understanding of cGMP signaling and as new therapies evolve to elevate cGMP levels, we provide a short methodological primer for measuring cGMP and cGMP-mediated vascular relaxation for investigators. • Nitric oxide (•NO) stimulates soluble guanylyl cyclase (sGC) to catalyze the production of cyclic guanosine 3′, 5′-monophosphate (cGMP) • We provide general guidelines for assessing sGC-cGMP signaling pathway in cells and tissue as well as measuring ex vivo •NO-sGC-cGMP mediated vascular relaxation • By combining cell and tissue-based measurements of cGMP and myography, one can rigorously assess the impact of new physiological factors and pharmacological modulators that influence •NO -cGMP signaling [ABSTRACT FROM AUTHOR]

Fibromuscular dysplasia is a nonatheromatous, noninflammatory arterial disorder that results in stenosis and/or aneurysm formation and rarely involves the mesenteric arteries. Herein, we report a case of fibromuscular dysplasia limited to the inferior mesenteric artery, which manifested with arterial aneurysms and ischemic colitis.

Ethnopharmacological Relevance: Tea (Camellia sinensis) is a favorite drink worldwide. Tea extracts and green tea main component (-)-epigallocatechin gallate (EGCG) are recommended for various vascular diseases. Anji white tea is a very popular green tea. Its vascular effect profile, the mechanisms, and the contribution of EGCG to its integrated effect need elucidation., Aim: To characterize the vasomotion effects of Anji white tea and EGCG, and to explore possible involvement of voltage-gated Ca 2+ channels (VGCCs) and voltage-gated K + (Kv) channels in their vasomotion effects., Materials and Methods: Anji white tea water soaking solution (AJWT) was prepared as daily tea-making process and concentrated to a concentration amounting to 200 mg/ml of dry tea leaves. The tension of rat arteries including aorta, coronary artery (RCA), cerebral basilar artery (CBA), intrarenal artery (IRA), intrapulmonary artery (IPA) and mesenteric artery (MA) was recorded with myographs. In arterial smooth muscle cells (ASMCs) freshly isolated from RCA, the levels of intracellular Ca 2+ were measured with Ca 2+ -sensitive fluorescent probe fluo 4-AM, and Kv currents were recorded with patch clamp. The expressions of VGCCs and Kv channels were assayed with RT-qPCR and immunofluorescence staining., Results: At 0.4-12.8 mg/ml of dry tea leaves, AJWT profoundly relaxed all tested arteries precontracted with various vasoconstrictors about half with a small transient potentiation on the precontractions before the relaxation. KCl-induced precontraction was less sensitive than precontractions induced by phenylephrine (PE), U46619 and serotonin (5-HT). IPA was less sensitive to the relaxation compared with other arteries. AJWT pretreatment for 1 h, 24 h and 72 h time-dependently inhibited the contractile responses of RCAs. In sharp contrast, at equivalent concentrations according to its content in AJWT, EGCG intensified the precontractions in most small arteries, except that it induced relaxation in PE-precontracted aorta and MA, U46619-precontracted aorta and CBA. EGCG pretreatment for 1 h and 24 h did not significantly affect RCA contractile responses. In RCA ASMCs, AJWT reduced, while EGCG enhanced, intracellular Ca 2+ elevation induced by depolarization which activates VGCCs. Patch clamp study showed that both AJWT and EGCG reduced Kv currents. RT-qPCR and immunofluorescence staining demonstrated that both AJWT and EGCG reduced the expressions of VGCCs and Kv channels., Conclusion: AJWT, but not EGCG, consistently induces vasorelaxation. The vasomotion effects of either AJWT or EGCG vary with arterial beds and vasoconstrictors. Modulation of VGCCs, but not Kv channels, contributes to AJWT-induced vasorelaxation. It is suggested that Anji white tea water extract instead of EGCG may be a promising food supplement for vasospastic diseases., Competing Interests: Declaration of competing interest We certify that there is no conflict of interest regarding this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K+-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein. To this end, 3 different types of ET-CORMs that either contain acetate (rac - 1 and rac - 4) or pivalate (rac - 8) as ester functionality, were tested ex vivo on methoxamine pre-contracted small rat mesenteric arteries in a myograph setting. Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs (rac - 1 and rac - 4), while treatment with the pivalate containing ET-CORM (rac - 8) resulted in no vasodilation. Pre-treatment of mesenteric arteries with the sGC inhibitor ODQ abolished rac - 4 mediated vasodilation, similar as for the known sGC activator SNP. Likewise, rac - 4 mediated vasodilation did not occur in KCL pretreated mesenteric arteries. Although mesenteric arteries abundantly expressed a variety of K+-channels only Kv7 channels were found to be of functional relevance for rac - 4 mediated vasodilation. In conclusion the current results identified Kv7 channels as the main channel by which rac - 4 mediates vasodilation. In keeping with the central role of Kv7 in the control of vascular tone and peripheral resistance these promising ex-vivo data warrant further in vivo studies, particularly in models of primary hypertension or cardiac diseases, to assess the potential use of ET-CORMs in these diseases. [ABSTRACT FROM AUTHOR]

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K+-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein. To this end, 3 different types of ET-CORMs that either contain acetate (rac-1 and rac-4) or pivalate (rac-8) as ester functionality, were tested ex vivo on methoxamine pre-contracted small rat mesenteric arteries in a myograph setting. Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs (rac-1 and rac-4), while treatment with the pivalate containing ET-CORM (rac-8) resulted in no vasodilation. Pre-treatment of mesenteric arteries with the sGC inhibitor ODQ abolished rac-4 mediated vasodilation, similar as for the known sGC activator SNP. Likewise, rac-4 mediated vasodilation did not occur in KCL pretreated mesenteric arteries. Although mesenteric arteries abundantly expressed a variety of K+-channels only Kv7 channels were found to be of functional relevance for rac-4 mediated vasodilation. In conclusion the current results identified Kv7 channels as the main channel by which rac-4 mediates vasodilation. In keeping with the central role of Kv7 in the control of vascular tone and peripheral resistance these promising ex-vivo data warrant further in vivo studies, particularly in models of primary hypertension or cardiac diseases, to assess the potential use of ET-CORMs in these diseases.

Objective: A practical screening tool for chronic mesenteric ischemia (CMI) could facilitate early recognition and reduce undertreatment and diagnostic delay. This study explored the ability to discriminate CMI from non-CMI patients with a mesenteric artery calcium score (MACS). Methods: This retrospective study included CTAs of consecutive patients with suspected CMI in a tertiary referral center between April 2016 and October 2019. A custom-built software module, using the Agatston definition, was developed and used to calculate the MACS for the celiac artery (CA), superior mesenteric artery (SMA), and inferior mesenteric artery. Scoring was performed by two blinded observers. Interobserver agreement was determined using 39 CTAs scored independently by both observers. CMI was defined as sustained symptom improvement after treatment. Non-CMI patients were patients not diagnosed with CMI after a diagnostic workup and patients not responding to treatment. Results: The MACS was obtained in 184 patients, 49 CMI and 135 non-CMI. Interobserver agreement was excellent (intraclass correlation coefficient 0.910). The MACS of all mesenteric arteries was significantly higher in CMI patients than in non-CMI patients. ROC analysis of the combined MACS of CA + SMA showed an acceptable AUC (0.767), high sensitivity (87.8%), and high NPV (92.1%), when using a ≥ 29.7 CA + SMA MACS cutoff. Comparison of two CTAs, obtained in the same patient at different points in time with different scan and reconstruction parameters, was performed in 29 patients and revealed significant differences in MACSs. Conclusion: MACS seems a promising screening method for CMI, but correction for scan and reconstruction parameters is warranted. Key Points: • A mesenteric artery calcium score obtained in celiac artery and superior mesenteric artery has a high negative predictive value for chronic mesenteric ischemia and could serve as a screening tool. • Interobserver agreement of the mesenteric artery calcium score is excellent. • Scan and reconstruction parameters influence the mesenteric artery calcium score and warrant the development of a method to correct for these parameters. [ABSTRACT FROM AUTHOR]

BackgroundCases of necrotizing enterocolitis occurring within 48 h of packed red blood cell (PRBC) transfusions are increasingly being described in observational studies. Transfusion-associated gut injury is speculated to result from an abnormal mesenteric vascular response to transfusion. However, the mechanism of disruption of the balance between mesenteric vasoconstriction and relaxation following transfusion is not known.MethodsPreterm lambs (n = 16, 134 d gestation; term: 145-147 d) were delivered and ventilated for 24 h. All the lambs received orogastric feeds with colostrum. In addition, 10 of these lambs received PRBC transfusions. Vasoreactivity was evaluated in isolated mesenteric arterial rings using norepinephrine and endothelin-1 as vasoconstrictors. Endothelium-dependent (A23187, a calcium ionophore) and endothelium-independent (SNAP) nitric oxide (NO) donors were used as vasorelaxants. Mesenteric arterial endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase 5 (PDE5) mRNA analyses and protein assays were performed.ResultsTransfusion with PRBC significantly increased mesenteric vasoconstriction to norepinephrine and endothelin-1 and impaired relaxation to A23187 and SNAP. Mesenteric arterial eNOS protein decreased following PRBC transfusion. No significant changes were noted in sGC and PDE5 mRNA or protein assays.ConclusionPRBC transfusion in enterally fed preterm lambs promotes mesenteric vasoconstriction and impairs vasorelaxation by reducing mesenteric arterial eNOS.

Purposes: Since the role of store-operated calcium entry (SOCE) in endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of mesenteric arteries in health and colitis is not fully understood, cyclopiazonic acid (CPA), a specific inhibitor of the sarco(endo) plasmic reticulum calcium-ATPases (SERCA), was used as a SOCE activator to investigate its role in normal mice and its alteration in colitis mice.Methods: The changes in Ca2+ signaling in vascular endothelial cells (VEC) were examined by single cell Ca2+ imaging and tension of mesenteric arteries in response to CPA were examined using Danish DMT520A microvascular measuring system.Results: CPA activated the SOCE through depletion of the endoplasmic reticulum (ER) Ca2+ in endothelial cells. CPA had a concentration-dependent vasorelaxing effect in endothelium-intact mesenteric arteries, which was lost after endothelial removal. Both nitric oxide (NO) and prostacyclin (PGI2) inhibitors did not affect CPA-induced vasorelaxation; however, after both NO and PGI2 were inhibited, KCa channel blocker [10 mM tetraethylammonium chloride (TEA)] inhibited CPA-induced vasorelaxation while KCa channel activator (0.3 μM SKA-31) promoted it. Two SOCE blockers [30 μM SKF96365 and 100 μM flufenamic acid (FFA)], and an Orai channel blocker (30 μM GSK-7975A) inhibited this vasorelaxation. The inhibition of both Na+/K+-ATPase (NKA) and Na+/Ca2+-exchange (NCX) also inhibited CPA-induced vasorelaxation. Finally, the CPA involved in EDH-induced vasorelaxation by the depletion of ER Ca2+ of mesenteric arteries was impaired in colitis mice.Conclusion: Depletion of ER Ca2+ by CPA induces a vasorelaxation of mesenteric arteries that is mediated through EDH mechanism and invokes the activation of SOCE. The CPA-induced endothelium-dependent dilation is impaired in colitis which may limit blood perfusion to the intestinal mucosa.

Purposes : Since the role of store-operated calcium entry (SOCE) in endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of mesenteric arteries in health and colitis is not fully understood, cyclopiazonic acid (CPA), a specific inhibitor of the sarco(endo) plasmic reticulum calcium-ATPases (SERCA), was used as a SOCE activator to investigate its role in normal mice and its alteration in colitis mice. Methods : The changes in Ca2+ signaling in vascular endothelial cells (VEC) were examined by single cell Ca2+ imaging and tension of mesenteric arteries in response to CPA were examined using Danish DMT520A microvascular measuring system. Results : CPA activated the SOCE through depletion of the endoplasmic reticulum (ER) Ca2+ in endothelial cells. CPA had a concentration-dependent vasorelaxing effect in endothelium-intact mesenteric arteries, which was lost after endothelial removal. Both nitric oxide (NO) and prostacyclin (PGI2) inhibitors did not affect CPA-induced vasorelaxation; however, after both NO and PGI2 were inhibited, KCa channel blocker [10 mM tetraethylammonium chloride (TEA)] inhibited CPA-induced vasorelaxation while KCa channel activator (0.3 μM SKA-31) promoted it. Two SOCE blockers [30 μM SKF96365 and 100 μM flufenamic acid (FFA)], and an Orai channel blocker (30 μM GSK-7975A) inhibited this vasorelaxation. The inhibition of both Na+/K+-ATPase (NKA) and Na+/Ca2+-exchange (NCX) also inhibited CPA-induced vasorelaxation. Finally, the CPA involved in EDH-induced vasorelaxation by the depletion of ER Ca2+ of mesenteric arteries was impaired in colitis mice. Conclusion : Depletion of ER Ca2+ by CPA induces a vasorelaxation of mesenteric arteries that is mediated through EDH mechanism and invokes the activation of SOCE. The CPA-induced endothelium-dependent dilation is impaired in colitis which may limit blood perfusion to the intestinal mucosa. [ABSTRACT FROM AUTHOR]