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Automated quantification of microvascular perfusion.
McClatchey PM, Mignemi NA, Xu Z, Williams IM, Reusch JEB, McGuinness OP, Wasserman DH
(2018) Microcirculation 25: e12482
MeSH Terms: Animals, Automation, Blood Flow Velocity, Hematocrit, Mice, Microcirculation, Microscopy, Fluorescence, Microscopy, Video, Microvessels, Perfusion, Phenylephrine, Reproducibility of Results, Saline Solution, Software
Show Abstract · Added March 26, 2019
OBJECTIVE - Changes in microvascular perfusion have been reported in many diseases, yet the functional significance of altered perfusion is often difficult to determine. This is partly because commonly used techniques for perfusion measurement often rely on either indirect or by-hand approaches.
METHODS - We developed and validated a fully automated software technique to measure microvascular perfusion in videos acquired by fluorescence microscopy in the mouse gastrocnemius. Acute perfusion responses were recorded following intravenous injections with phenylephrine, SNP, or saline.
RESULTS - Software-measured capillary flow velocity closely correlated with by-hand measured flow velocity (R = 0.91, P < 0.0001). Software estimates of capillary hematocrit also generally agreed with by-hand measurements (R = 0.64, P < 0.0001). Detection limits range from 0 to 2000 μm/s, as compared to an average flow velocity of 326 ± 102 μm/s (mean ± SD) at rest. SNP injection transiently increased capillary flow velocity and hematocrit and made capillary perfusion more steady and homogenous. Phenylephrine injection had the opposite effect in all metrics. Saline injection transiently decreased capillary flow velocity and hematocrit without influencing flow distribution or stability. All perfusion metrics were temporally stable without intervention.
CONCLUSIONS - These results demonstrate a novel and sensitive technique for reproducible, user-independent quantification of microvascular perfusion.
© 2018 John Wiley & Sons Ltd.
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14 MeSH Terms
The Vasculature in Prediabetes.
Wasserman DH, Wang TJ, Brown NJ
(2018) Circ Res 122: 1135-1150
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Vessels, Cardiovascular Diseases, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Disease Progression, Endothelium, Vascular, Extracellular Matrix, Fatty Acids, Nonesterified, Fibrinolysis, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Inflammation, Insulin Resistance, Life Style, Metabolic Syndrome, Mice, MicroRNAs, Microcirculation, Muscle, Skeletal, Obesity, Prediabetic State, Risk, Weight Loss
Show Abstract · Added March 26, 2019
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.
© 2018 American Heart Association, Inc.
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28 MeSH Terms
New paradigms in sepsis: from prevention to protection of failing microcirculation.
Hawiger J, Veach RA, Zienkiewicz J
(2015) J Thromb Haemost 13: 1743-56
MeSH Terms: Animals, Genetic Predisposition to Disease, Genome, Bacterial, Genome, Fungal, Genome, Viral, Host-Pathogen Interactions, Humans, Inflammation Mediators, Microcirculation, Microvessels, Phenotype, Risk Factors, Sepsis, Signal Transduction, Treatment Outcome
Show Abstract · Added October 4, 2015
Sepsis, also known as septicemia, is one of the 10 leading causes of death worldwide. The rising tide of sepsis due to bacterial, fungal and viral infections cannot be stemmed by current antimicrobial therapies and supportive measures. New paradigms for the mechanism and resolution of sepsis and consequences for sepsis survivors are emerging. Consistent with Benjamin Franklin's dictum 'an ounce of prevention is worth a pound of cure', sepsis can be prevented by vaccinations against pneumococci and meningococci. Recently, the NIH NHLBI Panel redefined sepsis as 'severe endothelial dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure'. Microvascular endothelial injury underlies sepsis-associated hypotension, edema, disseminated intravascular coagulation, acute respiratory distress syndrome and acute kidney injury. Microbial genome products trigger 'genome wars' in sepsis that reprogram the human genome and culminate in a 'genomic storm' in blood and vascular cells. Sepsis can be averted experimentally by endothelial cytoprotection through targeting nuclear signaling that mediates inflammation and deranged metabolism. Endothelial 'rheostats' (e.g. inhibitors of NF-κB, A20 protein, CRADD/RAIDD protein and microRNAs) regulate endothelial signaling. Physiologic 'extinguishers' (e.g. suppressor of cytokine signaling 3) can be replenished through intracellular protein therapy. Lipid mediators (e.g. resolvin D1) hasten sepsis resolution. As sepsis cases rose from 387 330 in 1996 to 1.1 million in 2011, and are estimated to reach 2 million by 2020 in the US, mortality due to sepsis approaches that of heart attacks and exceeds deaths from stroke. More preventive vaccines and therapeutic measures are urgently needed.
© 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
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15 MeSH Terms
Vasodilator-responsive idiopathic pulmonary arterial hypertension: evidence for a new disease?
Brittain EL, Hemnes AR
(2015) Ann Intern Med 162: 148-9
MeSH Terms: Capillaries, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Microcirculation, Vasodilator Agents
Added February 10, 2015
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7 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
The role of cytochrome P450 epoxygenases in retinal angiogenesis.
Capozzi ME, McCollum GW, Penn JS
(2014) Invest Ophthalmol Vis Sci 55: 4253-60
MeSH Terms: Animals, Animals, Newborn, Aryl Hydrocarbon Hydroxylases, Astrocytes, Cell Proliferation, Cells, Cultured, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Disease Models, Animal, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Developmental, Humans, Microcirculation, RNA, Messenger, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Retina, Retinal Neovascularization, Vascular Endothelial Growth Factor A
Show Abstract · Added February 19, 2015
PURPOSE - The purpose of this study was to investigate the role(s) of cytochrome P450 epoxygenases (CYPs) and their products, the epoxyeicosatrienoic acids (EETs), in hypoxia-induced VEGF production and pathologic retinal angiogenesis.
METHODS - Human retinal astrocytes, Müller cells, and retinal microvascular endothelial cells (HRMEC) were exposed to hypoxia, and relative CYP2C expression was measured by RT-PCR. Astrocyte and Müller cell VEGF production was measured by ELISA after exposure to hypoxia and treatment with the general CYP inhibitor, SKF-525a. Human retinal microvascular endothelial cells were treated with the CYP product, 11,12-epoxyeicosatrienoic acid [EET], or SKF-525a in the presence or absence of VEGF. Proliferation of HRMEC and tube formation were assayed. Oxygen-induced retinopathy (OIR) was induced in newborn rats. Retinal CYP2C11 and CYP2C23 expression were measured by RT-PCR. The OIR rats received SKF-525a by intravitreal injection and preretinal neovascularization (NV) was quantified. Retinal VEGF protein levels were measured by ELISA.
RESULTS - Human retinal astrocytes were the only cells to exhibit significant induction of CYP2C8 and CYP2C9 mRNA expression by hypoxia. Astrocytes, but not Müller cells, exhibited reduced hypoxia-induced VEGF production when treated with SKF-525a. 11,12-EET induced HRMEC proliferation and tube formation, and SKF-525a inhibited VEGF-induced proliferation. Oxygen-induced retinopathy induced expression of CYP2C23, but had no effect on CYP2C11. SKF-525a inhibited retinal NV and reduced retinal VEGF levels in OIR rats.
CONCLUSIONS - The CYP-derived 11,12-EET may exhibit a proangiogenic biological function in the retina following stimulation by hypoxia in astrocytes. Inhibition of CYP may provide a rational therapy against retinal NV, because it can reduce VEGF production and VEGF-induced angiogenic responses in endothelial cells.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
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23 MeSH Terms
Blood-brain barrier modeling with co-cultured neural progenitor cell-derived astrocytes and neurons.
Lippmann ES, Weidenfeller C, Svendsen CN, Shusta EV
(2011) J Neurochem 119: 507-20
MeSH Terms: Animals, Animals, Newborn, Astrocytes, Blood-Brain Barrier, Cell Differentiation, Cells, Cultured, Coculture Techniques, Endothelium, Vascular, Humans, Male, Microcirculation, Neurons, Rats, Rats, Sprague-Dawley, Stem Cells
Show Abstract · Added August 19, 2015
In vitro blood-brain barrier (BBB) models often consist of brain microvascular endothelial cells (BMECs) that are co-cultured with other cells of the neurovascular unit, such as astrocytes and neurons, to enhance BBB properties. Obtaining primary astrocytes and neurons for co-culture models can be laborious, while yield and heterogeneity of primary isolations can also be limiting. Neural progenitor cells (NPCs), because of their self-renewal capacity and ability to reproducibly differentiate into tunable mixtures of neurons and astrocytes, represent a facile, readily scalable alternative. To this end, differentiated rat NPCs were co-cultured with rat BMECs and shown to induce BBB properties such as elevated trans-endothelial electrical resistance, improved tight junction continuity, polarized p-glycoprotein efflux, and low passive permeability at levels indistinguishable from those induced by primary rat astrocyte co-culture. An NPC differentiation time of 12 days, with the presence of 10% fetal bovine serum, was found to be crucial for generating NPC-derived progeny capable of inducing the optimal response. This approach could also be extended to human NPC-derived astrocytes and neurons which similarly regulated BBB induction. The distribution of rat or human NPC-derived progeny under these conditions was found to be a roughly 3 : 1 mixture of astrocytes to neurons with varying degrees of cellular maturity. BMEC gene expression analysis was conducted using a BBB gene panel, and it was determined that 23 of 26 genes were similarly regulated by either differentiated rat NPC or rat astrocyte co-culture while three genes were differentially altered by the rat NPC-derived progeny. Taken together, these results demonstrate that NPCs are an attractive alternative to primary neural cells for use in BBB co-culture models.
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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15 MeSH Terms
Peripheral microvascular response to muscle contraction is unaltered by early diabetes but decreases with age.
Slade JM, Towse TF, Gossain VV, Meyer RA
(2011) J Appl Physiol (1985) 111: 1361-71
MeSH Terms: Adult, Age Factors, Arteries, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Exercise, Female, Humans, Hyperemia, Magnetic Resonance Imaging, Male, Microcirculation, Middle Aged, Muscle Contraction, Oxygen
Show Abstract · Added September 8, 2014
Long-term or untreated diabetes leads to micro- and macrovascular complications. However, there are few tests to evaluate microvascular function. A postcontraction blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) technique was exploited to measure peripheral microvascular function in diabetics and healthy controls matched with respect to age, body mass index, and physical activity. Postcontraction BOLD microvascular response was measured following 1-s maximal isometric ankle dorsiflexion in individuals with diabetes mellitus type I [DMI, n = 15, age 33 ± 3 yr (means ± SE), median diabetes duration = 5.5 yr] and type II (DMII, n = 16, age 45 ± 2 yr, median duration = 2.4 yr); responses were compared with controls (CONI and CONII). Peripheral macrovascular function of the popliteal and tibial arteries was assessed during exercise hyperemia with phase contrast magnetic resonance angiography following repetitive exercise. There were no group differences as a result of diabetes in peripheral microvascular function (peak BOLD response: DMI = 2.04 ± 0.38% vs. CONI = 2.08 ± 0.48%; DMII = 0.93 ± 0.24% vs. CONII = 1.13 ± 0.24%; mean ± SE), but the BOLD response was significantly influenced by age (partial r = -0.384, P = 0.003), supporting its sensitivity as a measure of microvascular function. Eleven individuals had no microvascular BOLD response, including three diabetics with neuropathy and four controls with a family history of diabetes. There were no differences in peripheral macrovascular function between groups when assessing exercise hyperemia or the pulsitility and resistive indexes. Although the BOLD microvascular response was not impaired in early diabetes, these results encourage further investigation of muscle BOLD as it relates to peripheral microvascular health.
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15 MeSH Terms
Postmaximal contraction blood volume responses are blunted in obese and type 2 diabetic subjects in a muscle-specific manner.
Sanchez OA, Copenhaver EA, Chance MA, Fowler MJ, Towse TF, Kent-Braun JA, Damon BM
(2011) Am J Physiol Heart Circ Physiol 301: H418-27
MeSH Terms: Adult, Blood Volume, Diabetes Mellitus, Type 2, Female, Humans, Isometric Contraction, Linear Models, Magnetic Resonance Imaging, Male, Microcirculation, Middle Aged, Muscle, Skeletal, Obesity, Oxygen, Oxygen Consumption, Oxyhemoglobins, Regional Blood Flow, Time Factors
Show Abstract · Added December 10, 2013
The purpose of this study was to determine whether there are differences in postisometric contraction blood volume and oxygenation responses among groups of type 2 diabetes mellitus (T2DM), obese, and lean individuals detectable using MRI. Eight T2DM patients were individually matched by age, sex, and race to non-T2DM individuals with similar body mass index (obese) and lean subjects. Functional MRI was performed using a dual-gradient-recalled echo, echo-planar imaging sequence with a repetition time of 1 s and at two echo times (TE = 6 and 46 ms). Data were acquired before, during, and after 10-s isometric dorsiflexion contractions performed at 50 and 100% of maximal voluntary contraction (MVC) force. MRI signal intensity (SI) changes from the tibialis anterior and extensor digitorum longus muscles were plotted as functions of time for each TE. From each time course, the difference between the minimum and the maximum postcontraction SI (ΔSI) were determined for TE = 6 ms (ΔSI(6)) and TE = 46 ms (ΔSI(46)), reflecting variations in blood volume and oxyhemoglobin saturation, respectively. Following 50% MVC contractions, the mean postcontraction ΔSI(6) values were similar in the three groups. Following MVC only, and in the EDL muscle only, T2DM and obese participants had ∼56% lower ΔSI(6) than the lean individuals. Also following MVC only, the ΔSI(46) response in the EDL was lower in T2DM subjects than in lean individuals. These data suggest that skeletal muscle small vessel impairment occurs in T2DM and body mass index-matched subjects, in muscle-specific and contraction intensity-dependent manners.
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18 MeSH Terms
Neonatal lung side population cells demonstrate endothelial potential and are altered in response to hyperoxia-induced lung simplification.
Irwin D, Helm K, Campbell N, Imamura M, Fagan K, Harral J, Carr M, Young KA, Klemm D, Gebb S, Dempsey EC, West J, Majka S
(2007) Am J Physiol Lung Cell Mol Physiol 293: L941-51
MeSH Terms: Animals, Animals, Newborn, Blood Vessels, Bronchopulmonary Dysplasia, Disease Models, Animal, Endothelial Cells, Humans, Hyperoxia, In Vitro Techniques, Infant, Newborn, Leukocyte Common Antigens, Lung, Mice, Mice, Inbred C57BL, Microcirculation, Stem Cells, Time Factors, Vascular Endothelial Growth Factor Receptor-2
Show Abstract · Added August 4, 2015
Lung side population (SP) cells are resident lung precursor cells with both epithelial and mesenchymal potential that are believed to play a role in normal lung development and repair. Neonatal hyperoxic exposure impairs lung development leading to a long-term decrease in gas exchange surfaces. The hypothesis that lung SP cells are altered during impaired lung development has not been studied. To address this issue, we characterized the endothelial potential of neonatal lung SP and subsets of lung SP from neonatal mice following hyperoxic exposure during room air recovery. Lung SP cells were isolated and sorted on the basis of their capacity to efflux Hoechst 33342. The lung SP was further sorted based on expression of Flk-1 and CD45. In vitro, both CD45(pos)/Flk-1(pos) and CD45(neg)/Flk-1(pos) bind isolectin B4 and incorporate LDL and form networks in matrigel, indicating that these populations have endothelial cell characteristics. Hyperoxic exposure of neonatal mice resulted in subtle changes in vascular and alveolar density on P13, which persisted with room air recovery to P41. During room air recovery, a decrease in lung SP cells was detected in the hyperoxic-exposed group on postnatal day 13 followed by an increase on day 41. Within this group, the lung SP subpopulation of cells expressing CD45 increased on day 21, 41, and 55. Here, we show that lung SP cells demonstrate endothelial potential and that the population distribution changes in number as well as composition following hyperoxic exposure. The hyperoxia-induced changes in lung SP cells may limit their ability to effectively contribute to tissue morphogenesis during room air recovery.
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18 MeSH Terms