scholarly journals Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shashi Kant ◽  
Siobhan M. Craige ◽  
Kai Chen ◽  
Michaella M. Reif ◽  
Heather Learnard ◽  
...  
Keyword(s):  
Blood Flow ◽  
Growth Factors ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Limb Ischemia ◽  
The United States ◽  
Hindlimb Ischemia ◽  
Peripheral Ischemia ◽  
Artery Disease

Abstract Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.

Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia

2021 ◽  
Author(s):  
Victoria Osinski ◽  
Prasad Srikakulapu ◽  
Young Min Haider ◽  
Melissa A. Marshall ◽  
Vijay C. Ganta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
B Cell ◽  
Peripheral Artery Disease ◽  
Myeloid Cell ◽  
Hindlimb Ischemia ◽  
Peripheral Artery ◽  
Artery Ligation ◽  
Artery Disease

Objective: Neovascularization can maintain and even improve tissue perfusion in the setting of limb ischemia during peripheral artery disease. The molecular and cellular mechanisms mediating this process are incompletely understood. We investigate the potential role(s) for Id3 (inhibitor of differentiation 3) in regulating blood flow in a murine model of hindlimb ischemia (HLI). Approach and Results: HLI was modeled through femoral artery ligation and resection and blood flow recovery was quantified by laser Doppler perfusion imaging. Mice with global Id3 deletion had significantly impaired perfusion recovery at 14 and 21 days of HLI. Endothelial- or myeloid cell-specific deletion of Id3 revealed no effect on perfusion recovery while B-cell–specific knockout of Id3 (Id3 BKO ) revealed a significant attenuation of perfusion recovery. Flow cytometry revealed no differences in ischemia-induced T cells or myeloid cell numbers at 7 days of HLI, yet there was a significant increase in B-1b cells in Id3 BKO . Consistent with these findings, ELISA demonstrated increases in skeletal muscle and plasma IgM. In vitro experiments demonstrated reduced proliferation and increased cell death when endothelial cells were treated with conditioned media from IgM-producing B-1b cells and tibialis anterior muscles in Id3 BKO mice showed reduced density of total CD31 + and αSMA + CD31 + vessels. Conclusions: This study is the first to demonstrate a role for B-cell–specific Id3 in maintaining blood flow recovery during HLI. Results suggest a role for Id3 in promoting blood flow during HLI and limiting IgM-expressing B-1b cell expansion. These findings present new mechanisms to investigate in peripheral artery disease pathogenesis.

scholarly journals Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

2021 ◽  
Vol 18 (2) ◽  
pp. 147916412199903
Author(s):  
Laura Croteau ◽  
Clément Mercier ◽  
Étienne Fafard-Couture ◽  
Alexandre Nadeau ◽  
Stéphanie Robillard ◽  
...  
Keyword(s):  
Blood Flow ◽  
Phosphatase Activity ◽  
Capillary Density ◽  
Artery Ligation ◽  
Vegf Signaling ◽  
Post Surgery ◽  
Src Homology ◽  
Artery Disease ◽  
Ischemic Muscle

Aims: Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling. Methods: Nondiabetic and diabetic mice, with ( ec-Prkcd−/−) or without ( ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs. Results: Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd−/− mice. VEGF signaling pathway was restored in diabetic ec-Prkcd−/− mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity. Conclusions: Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.

scholarly journals Use of Methyl Tert-Butyl Ether for the Treatment of Refractory Intrahepatic Biliary Strictures and Bile Casts: A Modern Perspective

2015 ◽  
Vol 2015 ◽  
pp. 1-3 ◽  
Author(s):  
Gregory Kim ◽  
Saninuj N. Malayaman ◽  
Michael Stuart Green
Keyword(s):  
Diethyl Ether ◽  
Treatment Options ◽  
Expectant Management ◽  
The United States ◽  
Methyl Tert Butyl Ether ◽  
Definitive Treatment ◽  
Team Approach ◽  
Butyl Ether ◽  
Tert Butyl

Cholelithiasis is a prevalent problem in the United States with 14% or more adults affected. Definitive treatment of cholelithiasis is cholecystectomy. When cholecystectomy yields minimal resolution treatment options include expectant management of asymptomatic gallstones or endoscopic retrograde cholangiopancreatogram. We present a case of intrahepatic biliary casts where surgical option was not possible, interventional radiology was unsuccessful, and methyl tert-butyl ether was used to dissolve the biliary obstruction. Dissolution therapy of gallstones was first reported in 1722 when Vollisnieri used turpentine in vitro. While diethyl ether has excellent solubilizing capacity, its low boiling point limited its use surgically as it vaporizes immediately. Diethyl ether can expand 120-fold during warming to body temperature after injection into the biliary system making it impractical for routine use. The use of dissolution is out of favor due to the success of laparoscopic cholecystectomy. Epidemiological studies have shown the general population should have minimal concerns from passive exposure. Dissolution using MTBE remains a viable option if surgical or endoscopic options are not available. However, because of risks involved to both the patient and the staff, careful multidisciplinary team approach must be undertaken to minimize the risks and provide the best possible care to the patient.

Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future

2021 ◽  
Author(s):  
Catherine Karbasiafshar ◽  
Frank W. Sellke ◽  
M. Ruhul Abid
Keyword(s):  
Stem Cell ◽  
Extracellular Vesicles ◽  
Treatment Options ◽  
Current Treatment ◽  
Lifestyle Changes ◽  
Challenges And Opportunities ◽  
Artery Disease ◽  
New Treatment

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery, However, recent revolutionary developments and insight into the potential of 'personalizing' EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies, and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.

Abstract 15630: Direct Renin Inhibition With Aliskiren Improves Ischemia-Induced Neovascularization

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michel Desjarlais ◽  
Sylvie Dussault ◽  
Wahiba Dhahri ◽  
Alain Rivard
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renin Angiotensin System ◽  
Cellular Migration ◽  
High Dose ◽  
Hindlimb Ischemia ◽  
Adhesive Properties ◽  
Tubule Formation ◽  
Renin Inhibition

Background: The activation of the renin-angiotensin system is associated with impaired formation of new blood vessels (neovascularization) in response to ischemia. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization following ischemia. Methods and Results: C57BL/6 mice were treated with a high dose of aliskiren (50 mg/kg), a low dose of aliskiren (10 mg/kg), or drinking water only. After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Treatment with aliskiren led to a significantly faster rate of blood flow recovery after hindlimb ischemia (Laser Doppler). Interestingly the lower dose of aliskiren, which did not reduce blood pressure, provided similar improvement of blood flow recuperation compared to the higher dose of aliskiren. At day 21 after surgery, Doppler flow ratios were significantly improved in mice treated with aliskiren (0.69+/-0.07 vs. 0.52+/-0.03; p<0.05). This was associated with an increased expression of angiogenic factors in ischemic muscles, including VEGF and eNOS. Endothelial progenitor cells (EPCs) have been shown to have an important role in postnatal neovascularisation. We found that aliskiren significantly increased the number of bone marrow EPCs at day 7 after ischemia (172+/-7% increase; p<0.05). Moreover, the adhesive properties of EPCs were significantly improved in mice treated with aliskiren (175+/-5% increase; p<0.05). In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (DAF staining), and a significant reduction of oxidative stress levels (DHE staining). Importantly, the antioxidant and angiogenic properties of aliskiren in HUVECs are abolished following treatment with the NOS inhibitor L-NAME. Conclusions: Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanisms involve beneficial effects of aliskiren on NO and angiogenic pathways in ischemic tissues, together with an increase in the number and the functional activity of EPCs.

Abstract 722: Treatment of Acute and Chronic Limb Ischemia with Intermedin (IMD) in Mouse Models

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Luyu Yao ◽  
Honglin Dong ◽  
Allen Gu ◽  
Xin Gu ◽  
Kai Yao ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Control Group ◽  
Silk Suture ◽  
Hindlimb Ischemia ◽  
Occlusion Model ◽  
Before And After ◽  
Artery Disease ◽  
The One

Objectives: This experiment proposes a novel mouse model to simulate long-term chronic ischemia caused by peripheral artery disease (PAD) using a partial ligation method to narrow down the femoral artery lumen in C57Bl/6 mice. This model will be compared to the typical occlusion model while testing Intermedin (IMD) as a possible treatment for ischemia. Methods: Partial hindlimb ligation technique: we use a strand of 11-0 nylon sutures to pierce the middle of the artery and suture half of the artery shut at both the proximal and distal end of the femoral artery. The typical occlusion model: we use a 7-0 silk suture to completely ligate the distal and proximal femoral artery. Hindlimb blood flow was monitored daily by Laser Doppler perfusion monitor before and after the surgery. IMD was administered at 150 μg/kg, ip, immediately following ligation and twice daily afterwards for up to one week, while in the control group saline was injected instead of IMD. Gastrocnemius muscle samples were collected at day 3 and day 7 for histology and molecular biology study. Results: Ischemic/non-ischemic leg blood perfusion ratio in the partial ligation model is significantly higher than in the typical model. It is also significantly increased in IMD-treated groups in both models. Compared to the tissue in complete ligation models, it is apparent that partial ligation model tissue is less severely affected upon initial ligation but maintains ischemia over the one week testing period as would be expected. Compared to the untreated ischemia groups in acute and chronic hindlimb ischemia models, IMD-treated animals had less severe ischemic injuries. Conclusion: Our study indicates that our chronic hindlimb ischemia model was successful with expected less ischemia status than complete occlusion. The partial occlusion model presented here more closely mimics human PAD, where atherosclerotic plaque builds up slowly, resulting in a lower pressure difference between the proximal and distal artery preventing adequate shunting of the blood into collateral circulation. Moreover, our study suggests that IMD has promise as a therapeutic treatment in acute and chronic hindlimb ischemia models to prevent necrosis in muscle tissue following ischemic events.

Upper-Extremity Arteries

2018 ◽  
pp. 219-236
Author(s):  
Adam Zybulewski ◽  
Ilya Livshitz ◽  
Bhumika Patel ◽  
Aaron Fischman
Keyword(s):  
Upper Extremity ◽  
Upper Limb ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Limb Ischemia ◽  
Arterial Injury ◽  
Arterial Access ◽  
Imaging Characteristics ◽  
Ischemic Syndrome

This chapter evaluates the spectrum of pathologic diseases that affect the upper-extremity arteries, their clinical manifestations, imaging characteristics, and treatment options. We review the role of surgical and endovascular intervention for the treatment of acute upper limb ischemia (AULI) and chronic upper limb ischemia (CULI), the clinical and imaging findings associated with Raynaud’s phenomenon, hypothenar hammer syndrome, distal hypoperfusion ischemic syndrome (DHIS), thromboangittis obliterans (TOA), thoracic outlet syndrome (TOS), giant cell arteritis, Bechet’s disease, radiation arteritis, and traumatic arterial injury, including compartment syndrome and pseudoanuerysm formation. Finally, the evolution of upper-extremity arterial access and use of transradial access (TRA), including benefits and risks, technique, and complications, are discussed.

scholarly journals Naegleria fowleri: Pathogenesis, Diagnosis, and Treatment Options

2015 ◽  
Vol 59 (11) ◽  
pp. 6677-6681 ◽  
Author(s):  
Eddie Grace ◽  
Scott Asbill ◽  
Kris Virga
Keyword(s):  
Case Reports ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Naegleria Fowleri ◽  
Content Type ◽  
High Profile ◽  
Free Living Amoeba ◽  
Nægleria Fowleri ◽  
Amoebic Meningoencephalitis

ABSTRACTNaegleria fowlerihas generated tremendous media attention over the last 5 years due to several high-profile cases. Several of these cases were followed very closely by the general public.N. fowleriis a eukaryotic, free-living amoeba belonging to the phylum Percolozoa.Naegleriaamoebae are ubiquitous in the environment, being found in soil and bodies of freshwater, and feed on bacteria found in those locations. WhileN. fowleriinfection appears to be quite rare compared to other diseases, the clinical manifestations of primary amoebic meningoencephalitis are devastating and nearly always fatal. Due to the rarity ofN. fowleriinfections in humans, there are no clinical trials to date that assess the efficacy of one treatment regimen over another. Most of the information regarding medication efficacy is based on either case reports orin vitrostudies. This review will discuss the pathogenesis, diagnosis, pharmacotherapy, and prevention ofN. fowleriinfections in humans, including a brief review of all survivor cases in North America.

Outgrowing Endothelial Cells That Are Derived from Human Umbilical Cord Blood Improve Neovascularization in Hind-Limb Ischemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3697-3697
Author(s):  
Eun-Sun Yoo ◽  
KiHwan Kwon ◽  
Jee-Young Ahn ◽  
Soo-Ah Oh ◽  
Hye-Jung Chang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cord Blood ◽  
Umbilical Cord Blood ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Hind Limb Ischemia

Abstract Backgroud: Human umbilical cord blood (UCB) contains a high number of endothelial progenitor cells (EPCs) and may be useful for the treatment of ischemic disease. Recently, we have isolated EPCs from UCB having different biologic properties for angiogenic capabilities in vitro. In this present study, the aim is to examine the usefulness of OECs in hind-limb ischemia. Methods: Mononuclear cells from UCB cultured using EGM-2 medium with VEGF, IGF-1 and FGF for 21 days. Early spindle-shaped cells (early OECs), which were grown during the first week of culture and late cobblestone shaped cells (late OECs), which were in peak growth during the third week of culture were found. The hind-limb ischemia was established as follows: Athymic nude mice (BALB/C-nu) 18–22 g in weight were anesthetized with pentobarbital (60 mg/kg) and their left femoral arteries and main extension arteries were operatively resected. To examine the effect of the vasculogenesis of the two types of OECs, the mice were divided into three groups (PBS, early and late OECs). Twenty-four hours after operative excision 5 × 105 OECs in 200 μl and an equal volume of PBS were administered by intramuscular injection into the mice on hind-limb ischemia. To compare the effect of OECs on neovascularization in vivo, the analysis of blood flow of ischemic and healthy hind limbs was performed on days 1 and 21 after surgery using near-infrared (NIR) imaging with incocyanne Green (ICG). Results: Late OECs expressed a high level of mRNA on endothelial marker genes and formed capillary tubes in Matrigel plates. The early spindle cells excreted more angiogenic cytokines and had more migratory ability. We divided the mice into two groups according to the degree of perfusion; good (22.5–50%/min) and poor (0–22.5%) perfusion. OECs improved the blood flow of the ischemic hind-limb in the ’good’ perfusion group but not in the ’poor’ perfusion group. Early OECs led to a more significant improvement in blood flow than that of the late OECs. Conclusion: The different types of OECs from UCB have different biologic properties in vitro and different vasculogenic potential in vivo as well. The results might have potential application for the treatment of hind-limb ischemia.

scholarly journals Carbon dioxide water-bath treatment augments peripheral blood flow through the development of angiogenesis

2017 ◽  
Vol 95 (8) ◽  
pp. 938-944 ◽  
Author(s):  
Yan-Jun Xu ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Blood Flow ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Water Bath ◽  
Peripheral Blood Flow ◽  
Vascular Endothelial ◽  
Peripheral Ischemia ◽  
Flow Through ◽  
Bath Therapy ◽  
Endothelial Growth Factor

In this study, we investigated the effects of CO2 water-bath therapy on blood flow and angiogenesis in the ischemic hind limb, as well as some plasma angiogenic factors in peripheral ischemic model. The hind limb ischemia was induced by occluding the femoral artery for 2 weeks in rats and treated with or without CO2 water-bath therapy at 37 °C for 4 weeks (20 min treatment every day for 5 days per week). The peak blood flow and minimal and mean blood flow in the ischemic skeletal muscle were markedly increased by the CO2 water-bath therapy. This increase in blood flow was associated with development of angiogenesis in the muscle, as well as reduction in the ischemia-induced increase in plasma malondialdehyde levels. Although plasma vascular endothelial growth factor and nitric oxide levels were increased in animals with peripheral ischemia, the changes in these biomarkers were not affected by CO2 water-bath therapy. These results suggest that augmentation of blood flow in the ischemic hind limb by CO2 water-bath therapy may be due to the development of angiogenesis and reduction in oxidative stress.

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