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Endothelial cells on an aged subendothelial matrix display heterogeneous strain profiles in silico.
Kohn JC, Abdalrahman T, Sack KL, Reinhart-King CA, Franz T
(2018) Biomech Model Mechanobiol 17: 1405-1414
MeSH Terms: Animals, Blood Vessels, Computer Simulation, Endothelial Cells, Extracellular Matrix, Male, Mice, Inbred C57BL, Models, Biological, Stress, Mechanical
Show Abstract · Added April 10, 2019
Within the artery intima, endothelial cells respond to mechanical cues and changes in subendothelial matrix stiffness. Recently, we found that the aging subendothelial matrix stiffens heterogeneously and that stiffness heterogeneities are present on the scale of one cell length. However, the impacts of these complex mechanical micro-heterogeneities on endothelial cells have not been fully understood. Here, we simulate the effects of matrices that mimic young and aged vessels on single- and multi-cell endothelial cell models and examine the resulting cell basal strain profiles. Although there are limitations to the model which prohibit the prediction of intracellular strain distributions in alive cells, this model does introduce mechanical complexities to the subendothelial matrix material. More heterogeneous basal strain distributions are present in the single- and multi-cell models on the matrix mimicking an aged artery over those exhibited on the young artery. Overall, our data indicate that increased heterogeneous strain profiles in endothelial cells are displayed in silico when there is an increased presence of microscale arterial mechanical heterogeneities in the matrix.
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Porcine Ischemic Wound-Healing Model for Preclinical Testing of Degradable Biomaterials.
Patil P, Martin JR, Sarett SM, Pollins AC, Cardwell NL, Davidson JM, Guelcher SA, Nanney LB, Duvall CL
(2017) Tissue Eng Part C Methods 23: 754-762
MeSH Terms: Animals, Biocompatible Materials, Blood Vessels, Disease Models, Animal, Ischemia, Macrophages, Materials Testing, Skin, Surgical Flaps, Sus scrofa, Tissue Scaffolds, Wound Healing
Show Abstract · Added March 14, 2018
Impaired wound healing that mimics chronic human skin pathologies is difficult to achieve in current animal models, hindering testing and development of new therapeutic biomaterials that promote wound healing. In this article, we describe a refinement and simplification of the porcine ischemic wound model that increases the size and number of experimental sites per animal. By comparing three flap geometries, we adopted a superior configuration (15 × 10 cm) that enabled testing of twenty 1 cm wounds in each animal: 8 total ischemic wounds within 4 bipedicle flaps and 12 nonischemic wounds. The ischemic wounds exhibited impaired skin perfusion for ∼1 week. To demonstrate the utility of the model for comparative testing of tissue regenerative biomaterials, we evaluated the healing process in wounds implanted with highly porous poly (thioketal) urethane (PTK-UR) scaffolds that were fabricated through reaction of reactive oxygen species (ROS)-cleavable PTK macrodiols with isocyanates. PTK-lysine triisocyanate (LTI) scaffolds degraded significantly in vitro under both oxidative and hydrolytic conditions whereas PTK-hexamethylene diisocyanate trimer (HDIt) scaffolds were resistant to hydrolytic breakdown and degraded exclusively through an ROS-dependent mechanism. Upon placement into porcine wounds, both types of PTK-UR materials fostered new tissue ingrowth over 10 days in both ischemic and nonischemic tissue. However, wound perfusion, tissue infiltration and the abundance of pro-regenerative, M2-polarized macrophages were markedly lower in ischemic wounds independent of scaffold type. The PTK-LTI implants significantly improved tissue infiltration and perfusion compared with analogous PTK-HDIt scaffolds in ischemic wounds. Both LTI and HDIt-based PTK-UR implants enhanced M2 macrophage activity, and these cells were selectively localized at the scaffold/tissue interface. In sum, this modified porcine wound-healing model decreased animal usage, simplified procedures, and permitted a more robust evaluation of tissue engineering materials in preclinical wound healing research. Deployment of the model for a relevant biomaterial comparison yielded results that support the use of the PTK-LTI over the PTK-HDIt scaffold formulation for future advanced therapeutic studies.
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12 MeSH Terms
Gallbladder Cancer Presenting with Jaundice: Uniformly Fatal or Still Potentially Curable?
Tran TB, Norton JA, Ethun CG, Pawlik TM, Buettner S, Schmidt C, Beal EW, Hawkins WG, Fields RC, Krasnick BA, Weber SM, Salem A, Martin RCG, Scoggins CR, Shen P, Mogal HD, Idrees K, Isom CA, Hatzaras I, Shenoy R, Maithel SK, Poultsides GA
(2017) J Gastrointest Surg 21: 1245-1253
MeSH Terms: Aged, Bilirubin, Blood Vessels, CA-19-9 Antigen, Drainage, Female, Gallbladder Neoplasms, Humans, Jaundice, Obstructive, Lymphatic Vessels, Male, Middle Aged, Neoplasm Invasiveness, Postoperative Complications, Reoperation, Survival Rate, United States
Show Abstract · Added April 10, 2018
BACKGROUND - Jaundice as a presenting symptom of gallbladder cancer has traditionally been considered to be a sign of advanced disease, inoperability, and poor outcome. However, recent studies have demonstrated that a small subset of these patients can undergo resection with curative intent.
METHODS - Patients with gallbladder cancer managed surgically from 2000 to 2014 in 10 US academic institutions were stratified based on the presence of jaundice at presentation (defined as bilirubin ≥4 mg/ml or requiring preoperative biliary drainage). Perioperative morbidity, mortality, and overall survival were compared between jaundiced and non-jaundiced patients.
RESULTS - Of 400 gallbladder cancer patients with available preoperative data, 108 (27%) presented with jaundice while 292 (73%) did not. The fraction of patients who eventually underwent curative-intent resection was much lower in the presence of jaundice (n = 33, 30%) than not (n = 218, 75%; P < 0.001). Jaundiced patients experienced higher perioperative morbidity (69 vs. 38%; P = 0.002), including a much higher need for reoperation (12 vs. 1%; P = 0.003). However, 90-day mortality (6.5 vs. 3.6%; P = 0.35) was not significantly higher. Overall survival after resection was worse in jaundiced patients (median 14 vs. 32 months; P < 0.001). Further subgroup analysis within the jaundiced patients revealed a more favorable survival after resection in the presence of low CA19-9 < 50 (median 40 vs. 12 months; P = 0.003) and in the absence of lymphovascular invasion (40 vs. 14 months; P = 0.014).
CONCLUSION - Jaundice is a powerful preoperative clinical sign of inoperability and poor outcome among gallbladder cancer patients. However, some of these patients may still achieve long-term survival after resection, especially when preoperative CA19-9 levels are low and no lymphovascular invasion is noted pathologically.
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The Vascular Wall: a Plastic Hub of Activity in Cardiovascular Homeostasis and Disease.
Awgulewitsch CP, Trinh LT, Hatzopoulos AK
(2017) Curr Cardiol Rep 19: 51
MeSH Terms: Blood Vessels, Cardiovascular Diseases, Cell Differentiation, Cell Lineage, Cell Plasticity, Epithelial-Mesenchymal Transition, Homeostasis, Humans, Stem Cells
Show Abstract · Added September 6, 2017
PURPOSE OF REVIEW - This review aims to summarize recent findings regarding the plasticity and fate switching among somatic and progenitor cells residing in the vascular wall of blood vessels in health and disease.
RECENT FINDINGS - Cell lineage tracing methods have identified multiple origins of stem cells, macrophages, and matrix-producing cells that become mobilized after acute or chronic injury of cardiovascular tissues. These studies also revealed that in the disease environment, resident somatic cells become plastic, thereby changing their stereotypical identities to adopt proinflammatory and profibrotic phenotypes. Currently, the functional significance of this heterogeneity among reparative cells is unknown. Furthermore, mechanisms that control cellular plasticity and fate decisions in the disease environment are poorly understood. Cardiovascular diseases are responsible for the majority of deaths worldwide. From a therapeutic perspective, these novel discoveries may identify new targets to improve the repair and regeneration of the cardiovascular system.
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9 MeSH Terms
Estrogen and insulin transport through the blood-brain barrier.
May AA, Bedel ND, Shen L, Woods SC, Liu M
(2016) Physiol Behav 163: 312-321
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Blood Vessels, Blood-Brain Barrier, Body Weight, Brain, Dietary Fats, Estrogens, Female, Glucose Transporter Type 1, Insulin, Insulin Resistance, Male, Obesity, Ovariectomy, Rats, Rats, Long-Evans, Synaptophysin
Show Abstract · Added March 2, 2017
Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS.
Copyright © 2016 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis.
Paik DT, Rai M, Ryzhov S, Sanders LN, Aisagbonhi O, Funke MJ, Feoktistov I, Hatzopoulos AK
(2015) Circ Res 117: 804-16
MeSH Terms: Angiopoietin-1, Animals, Arterioles, Blood Vessels, Blotting, Western, Cell Line, Cell Proliferation, Cells, Cultured, Endothelial Cells, Fibrosis, Gene Expression, Humans, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Muscle, Smooth, Vascular, Myocardium, Myocytes, Cardiac, Myocytes, Smooth Muscle, Myofibroblasts, NF-kappa B, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor Receptor-2, Wnt Proteins
Show Abstract · Added February 23, 2016
RATIONALE - Myocardial infarction causes irreversible tissue damage, leading to heart failure. We recently discovered that canonical Wnt signaling and the Wnt10b ligand are strongly induced in mouse hearts after infarction. Wnt10b regulates cell fate in various organs, but its role in the heart is unknown.
OBJECTIVE - To investigate the effect of Wnt10b gain-of-function on cardiac repair mechanisms and to assess its potential to improve ventricular function after injury.
METHODS AND RESULTS - Histological and molecular analyses showed that Wnt10b is expressed in cardiomyocytes and localized in the intercalated discs of mouse and human hearts. After coronary artery ligation or cryoinjury in mice, Wnt10b is strongly and transiently induced in peri-infarct cardiomyocytes during granulation tissue formation. To determine the effect of Wnt10b on neovascularization and fibrosis, we generated a mouse line to increase endogenous Wnt10b levels in cardiomyocytes. We found that gain of Wnt10b function orchestrated a recovery phenotype characterized by robust neovascularization of the injury zone, less myofibroblasts, reduced scar size, and improved ventricular function compared with wild-type mice. Wnt10b stimulated expression of vascular endothelial growth factor receptor 2 in endothelial cells and angiopoietin-1 in vascular smooth muscle cells through nuclear factor-κB activation. These effects coordinated endothelial growth and smooth muscle cell recruitment, promoting robust formation of large, coronary-like blood vessels.
CONCLUSION - Wnt10b gain-of-function coordinates arterial formation and attenuates fibrosis in cardiac tissue after injury. Because generation of mature blood vessels is necessary for efficient perfusion, our findings could lead to novel strategies to optimize the inherent repair capacity of the heart and prevent the onset of heart failure.
© 2015 American Heart Association, Inc.
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25 MeSH Terms
Broad targeting of angiogenesis for cancer prevention and therapy.
Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK, Generali D, Nagaraju GP, El-Rayes B, Ribatti D, Chen YC, Honoki K, Fujii H, Georgakilas AG, Nowsheen S, Amedei A, Niccolai E, Amin A, Ashraf SS, Helferich B, Yang X, Guha G, Bhakta D, Ciriolo MR, Aquilano K, Chen S, Halicka D, Mohammed SI, Azmi AS, Bilsland A, Keith WN, Jensen LD
(2015) Semin Cancer Biol 35 Suppl: S224-S243
MeSH Terms: Angiogenesis Inhibitors, Antineoplastic Agents, Phytogenic, Blood Vessels, Cell Proliferation, Humans, Immunotherapy, Neoplasms, Neovascularization, Pathologic
Show Abstract · Added October 17, 2015
Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
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8 MeSH Terms
Vascular content, tone, integrity, and haemodynamics for guiding fluid therapy: a conceptual approach.
Chawla LS, Ince C, Chappell D, Gan TJ, Kellum JA, Mythen M, Shaw AD, ADQI XII Fluids Workgroup
(2014) Br J Anaesth 113: 748-55
MeSH Terms: Blood Vessels, Delphi Technique, Dialysis, Fluid Therapy, Hemodynamics, Humans, Microcirculation, Perfusion, Regional Blood Flow, Sepsis
Show Abstract · Added October 20, 2015
BACKGROUND - Despite many clinical trials and investigative efforts to determine appropriate therapeutic intervention(s) for shock, this topic remains controversial. The use of i.v. fluid has represented the cornerstone for the treatment of hypoperfusion for two centuries.
METHODS - As a part of International Acute Dialysis Quality Initiative XII Fluids Workgroup meeting, we sought to incorporate recent advances in our understanding of vascular biology into a more comprehensive yet accessible approach to the patient with hypoperfusion. In this workgroup, we attempted to develop a framework that incorporates key aspects of the vasculature into a diagnostic approach.
RESULTS - The four main components of our proposal involve the assessment of the blood flow (BF), vascular content (vC), the vascular barrier (vB), and vascular tone (vT). Any significant perturbation in any of these domains can lead to hypoperfusion at both the macro- and micro-circulatory level. We have termed the BF, vC, vB, and vT diagnostic approach the vascular component (VC) approach.
CONCLUSIONS - The VC approach to hypoperfusion has potential advantages to the current diagnostic system. This approach also has the distinct advantage that it can be used to assess the systemic, regional, and micro-vasculature, thereby harmonizing the approach to clinical vascular diagnostics across these levels. The VC approach will need to be tested prospectively to determine if this system can in fact improve outcomes in patients who suffer from hypoperfusion.
© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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10 MeSH Terms
Is there a new dawn for selective mineralocorticoid receptor antagonism?
Luther JM
(2014) Curr Opin Nephrol Hypertens 23: 456-61
MeSH Terms: Animals, Antihypertensive Agents, Blood Pressure, Blood Vessels, Drug Design, Humans, Hyperkalemia, Hypertension, Mineralocorticoid Receptor Antagonists, Receptors, Mineralocorticoid, Risk Factors, Signal Transduction, Treatment Outcome
Show Abstract · Added October 27, 2014
PURPOSE OF REVIEW - Aldosterone and the mineralocorticoid receptor contribute to resistant hypertension and cardiovascular mortality, and mineralocorticoid receptor antagonists effectively reduce these complications. Their use is limited in certain populations with a higher risk of hyperkalemia or renal dysfunction. This review will highlight recent developments in extra-renal mineralocorticoid receptor research and the development of novel mineralocorticoid receptor antagonists.
RECENT FINDINGS - Tissue-specific knockout-out models provide definitive evidence that the vascular mineralocorticoid receptor directly contributes to hypertension and vascular remodeling, independent of renal effects. Several nonsteroidal mineralocorticoid receptor antagonists are in preclinical development or early-stage clinical trials. Several nonsteroidal mineralocorticoid receptor antagonists have demonstrated preserved cardiovascular benefit with a reduced incidence of hyperkalemia in preclinical studies.
SUMMARY - Novel, potent nonsteroidal mineralocorticoid receptor antagonists are in development, although their effect on cardiovascular and adverse drug events requires further investigation.
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13 MeSH Terms
Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans.
Kawasaki K, Freimuth J, Meyer DS, Lee MM, Tochimoto-Okamoto A, Benzinou M, Clermont FF, Wu G, Roy R, Letteboer TG, Ploos van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Westermann CJ, Coffey RJ, Akhurst RJ
(2014) Proc Natl Acad Sci U S A 111: 7723-8
MeSH Terms: ADAM Proteins, ADAM17 Protein, Animals, Blood Vessels, Gene Expression Regulation, Genetic Variation, Humans, Immunohistochemistry, Luciferases, Mice, Mice, Inbred C57BL, NIH 3T3 Cells, Signal Transduction, Smad2 Protein, Transforming Growth Factor beta, Transforming Growth Factor beta1
Show Abstract · Added February 19, 2015
Outcome of TGFβ1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFβ1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b(C57) haplotype suppresses prenatal lethality of Tgfb1(-/-) embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFβRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFβRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFβR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFβ signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFβ/bone morphogenetic protein receptor genes, ENG, encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFβ-regulated vascular disease.
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16 MeSH Terms