Modulation Of Blood Flow Research Articles

Morphological Signs of Intravital Contraction (Retraction) of Pulmonary Thrombotic Emboli

The goal of the study was to establish whether contraction (retraction) of thrombi and/or thrombotic emboli occurs in vivo using morphological signs of blood clot compression, such as characteristic deformation of erythrocytes and redistribution of fibrin toward the surface of a thrombus/embolus. Three postmortem human pulmonary thrombotic emboli were examined by scanning electron microscopy and light microscopy after staining with hematoxylin and eosin as well as with Mallory’s stain. In two pulmonary emboli, which were extracted at 7 and 15 h after death of the patients, compressed polyhedral erythrocytes (polyhedrocytes) were revealed that were formed due to mechanical deformation under the action of contractile forces generated by activated platelets. In addition, the uneven distribution of fibrin within the emboli was found with accumulation of fibrin at the periphery of the emboli, which is another structural characteristic of a contracted blood clot. In one of the three emboli analyzed, which was extracted 38 h after the patient’s death (the “oldest” embolus), the morphological signs of contraction were absent, which was likely related to the partial postmortem autolysis of the embolus or intravital impairment of contraction. The ex vivo thrombotic emboli have morphological signs of clot contraction, suggesting intravital compression of the primary thrombi and/or thrombotic emboli. The in vivo contraction of thrombi and emboli may be an important pathogenic mechanism for modulation of blood flow past otherwise obstructive clots at the sites of thrombotic occlusion of a vessel. The presence of compressed erythrocytes inside and the predominant location of fibrin around the periphery of a thrombus or embolus can potentially serve as additional pathomorphological criteria for the intravital contraction of thrombi and thrombotic emboli.

Endothelin-1 Regulation of Exercise-Induced Changes in Flow: Dynamic Regulation of Vascular Tone.

Although endothelin (ET)-1 is a highly potent vasoconstrictor with considerable efficacy in numerous vascular beds, the role of endogenous ET-1 in the regulation of vascular tone remains unclear. The perspective that ET-1 plays little role in the on-going regulation of vascular tone at least under physiologic conditions is supported by findings that potential ET-1 constriction is minimized by the release of the vasodilator and ET-1 synthesis inhibitor, nitric oxide (NO). Indeed, ET-1 release and constriction is self-limited by ET-1-induced, endothelial ETB receptor-mediated release of NO. Moreover, even if the balance between ET-1 and NO were reversed as the result of lowered NO activity, as occurs in a number of pathophysiologies associated with endothelial dysfunction, the well-known resistance of ET-1 constriction to reversal (as determined with exogenous ET-1) precludes ET-1 in the dynamic, i.e., moment-to-moment, regulation of vascular tone. On the other hand, and as presently reviewed, findings of ET-1-dependent modulation of organ blood flow with exercise under physiologic conditions demonstrate the dynamic regulation of vascular tone by ET-1. We speculate that this regulation is mediated at least in part through changes in ET-1 synthesis/release caused by pulsatile flow-induced shear stress and NO.

Do Evolutionary Changes in Astrocytes Contribute to the Computational Power of the Hominid Brain?

It is now well accepted that astrocytes are essential in all major nervous system functions of the rodent brain, including neurotransmission, energy metabolism, modulation of blood flow, ion and water homeostasis, and, indeed, higher cognitive functions, although the contribution of astrocytes in cognition is still in early stages of study. Here we review the most current research findings on human astrocytes, including their structure, molecular characterization, and functional properties. We also highlight novel tools that have been established for translational approaches to the comparative study of astrocytes from humans and experimental animals. Understanding the differences in astrocytes is essential to elucidate the contribution of astrocytes to normal physiology, cognitive processing and diverse pathologies of the central nervous system.

Effects of flow changes on radiotracer binding: Simultaneous measurement of neuroreceptor binding and cerebral blood flow modulation

The potential effects of changes in blood flow on the delivery and washout of radiotracers has been an ongoing question in PET bolus injection studies. This study provides practical insight into this topic by experimentally measuring cerebral blood flow (CBF) and neuroreceptor binding using simultaneous PET/MRI. Hypercapnic challenges (7% CO2) were administered to non-human primates in order to induce controlled increases in CBF, measured with pseudo-continuous arterial spin labeling. Simultaneously, dopamine D2/D3 receptor binding of [11C]raclopride or [18F]fallypride was monitored with dynamic PET. Experiments showed that neither time activity curves nor quantification of binding through binding potentials (BPND) were measurably affected by CBF increases, which were larger than two-fold. Simulations of experimental procedures showed that even large changes in CBF should have little effect on the time activity curves of radiotracers, given a set of realistic assumptions. The proposed method can be applied to experimentally assess the flow sensitivity of other radiotracers. Results demonstrate that CBF changes, which often occur due to behavioral tasks or pharmacological challenges, do not affect PET [11C]raclopride or [18F]fallypride binding studies and their quantification. The results from this study suggest flow effects may have limited impact on many PET neuroreceptor tracers with similar properties.

Locus coeruleus.

The locus coeruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the central nervous system. The LC-NE system has a major role in arousal, attention and stress responses. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis and control of local blood flow. The LC is severely affected in neurodegenerative disorders including Parkinson disease (PD). Involvement of the noradrenergic neurons of the LC precedes that of dopaminergic neurons of the substantia nigra pars compacta and has been increasingly recognized as a potential major contributor to cognitive manifestations in early PD, particularly impaired attention. Abnormal noradrenergic signaling may also potentially contribute to motor manifestations of the disease.This makes the LC-NE system a major contributor to the pathobiology and potential target for therapy of PD.

Astrocytes in a dish: Using pluripotent stem cells to model neurodegenerative and neurodevelopmental disorders.

Neuroscience and Neurobiology have historically been neuron biased, yet up to 40% of the cells in the brain are astrocytes. These cells are heterogeneous and regionally diverse but universally essential for brain homeostasis. Astrocytes regulate synaptic transmission as part of the tripartite synapse, provide metabolic and neurotrophic support, recycle neurotransmitters, modulate blood flow and brain blood barrier permeability and are implicated in the mechanisms of neurodegeneration. Using pluripotent stem cells (PSC), it is now possible to study regionalised human astrocytes in a dish and to model their contribution to neurodevelopmental and neurodegenerative disorders. The evidence challenging the traditional neuron-centric view of degeneration within the CNS is reviewed here, with focus on recent findings and disease phenotypes from human PSC-derived astrocytes. In addition we compare current protocols for the generation of regionalised astrocytes and how these can be further refined by our growing knowledge of neurodevelopment. We conclude by proposing a functional and phenotypical characterisation of PSC-derived astrocytic cultures that is critical for reproducible and robust disease modelling.

Training-Induced Modulation of Cerebral Blood Flow and Cognition

Training-Induced Modulation of Cerebral Blood Flow and Cognition

Cognitive and mood improvements following acute supplementation with purple grape juice in healthy young adults

PurposeBerry-derived phenolic compounds found in grapes have been associated with a number of health benefits, including the augmentation of human brain function and cognition. Previous intervention studies of Concord grape juice have demonstrated improvement to memory and driving ability following 3- to 4-month supplementation in middle-aged and older adults. However, no studies to date have demonstrated acute cognitive benefits of grape juice, and investigation of these effects in young adults is lacking.MethodsThis randomised, placebo-controlled, double-blind, counterbalanced-crossover study, assessed the effects of 230 ml purple grape juice or sugar-matched control in 20 healthy young adults. Computerised measures of episodic memory, working memory, attention and mood were completed at baseline and following a 20-min absorption period.ResultsPurple grape juice significantly improved reaction time on a composite attention measure (p = 0.047) and increased calm ratings (p = 0.046) when compared to placebo. Order effects also indicated an enduring positive effect on pre-dose memory reaction time (p = 0.018) and post-dose calm ratings (p = 0.019) when purple grape was consumed first.ConclusionsThese findings in a small sample of healthy young adults suggest that purple grape juice can acutely enhance aspects of cognition and mood. No significant effects of juice were observed on memory measures, suggesting that these may be less susceptible to manipulation following acute supplementation in healthy young adults. Potential mechanisms underlying these effects include modulation of cerebral blood flow, glucoregulation and inhibition of monoamine oxidase activity, all of which require further exploration.

Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis.

Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359-2372, 2017. © 2016 Wiley Periodicals, Inc.

Assessment of Cutaneous Microcirculation Autoregulation with Phase and Linear Based Eulerian Video Magnification

IntroductionThe identification of low frequency variations in blood pressure recordings date back to the mid‐1800's. The mechanism for the low frequency oscillation is associated with intrinsic myogenic activity of smooth muscle cells in resistance arteries. Therefore, local metabolic demand modulates blood flow distribution. Non‐invasive assessment of the microcirculation in dermatology, diabetes, skin‐graft, and burn‐injury patients could facilitate assessment of therapeutic interventions. Eulerian Video Magnification (EVM) software was developed by the Massachusetts Institute of Technology (MIT) to magnify subtle changes in motion and color in video recordings. Using this technology, magnification of a video recording may reveal local changes in the cutaneous human microcirculation.HypothesisWe hypothesize that EVM can be used to assess oscillations in cutaneous blood flow velocity.MethodsIRB approval was obtained to acquire physiological data from healthy graduate students (N = 10). Tissue Doppler was used to measure local changes in blood flow velocity on the forehead. Heart rate was assessed with an ECG and subjects breathed in time to a metronome (15 breaths/min) to normalize the effect of ventilation. Videos were processed using MIT's EVM Matlab code to magnify motion (Phase), or color & motion (Linear). All videos were magnified in the frequency range of interest (0.067–1.67 Hz; 4–100 cycles/min) to enhance human physiological frequencies. Gain was set to 50%; and a Gaussian filter was set to level 4. Phase magnification used a pyramid filtering scheme with octaves (1, ½, ¼) to specify the number of times the video is filtered; while linear magnification utilized chrominance attenuation to reduce color changes created by the magnification process. Red, green, and blue color spectrums extracted from magnified videos were analyzed with a Fast Fourier Transform (FFT) to identify magnified frequencies and power.ResultsPhase magnification (motion) and corresponding FFTs suggest strong correlations to heart rate and respiration rate but not tissue Doppler blood flow. On the other hand, linear magnification (color) and accompanying FFTs were strongly correlated to heart rate (r = 0.987; p = 0.001), respiration rate (r = 0.741; p = 0.014), and local tissue Doppler recordings (r = 0.945; p = 0.001).ConclusionThese preliminary data demonstrate that a video recording of a human subject can be magnified with EVM to assess heart rate, respiration rate, and regional blood flow velocity oscillations in the cutaneous microcirculation. EVM may be a useful non‐invasive modality to evaluate changes in microcirculation autoregulation in human subjects.Support or Funding InformationMidwestern University, Chicago College of Osteopathic Medicine, College of Health Sciences

Microcirulatory changes caused by experimental light induced desynchronosis

Cardiovascular diseases are the leading cause of disability and mortality in Russia, which determines the topicality of investigations devoted to risk factors of their development and progression. Considering the complex physiological regulatory mechanisms of the circulatory system, that cause circadian changes of its functioning, light-induced desynchronosis may act as one of the risk factors for cardiovascular disease. The aim of this study was to investigate the effect of light desynchronosis on the microcirculation in white rats. Materials and methods. The study was carried out on 20 white male rats, which were divided into two groups: experimental - 10 rats exposed to the change light-mode and control - animals in natural light-mode. Microcirculation was measured by laser Doppler flowmetry. Main results. At the stage of temporary mismatch (the first day of the experiment) microcirculation disorders were mild and manifested by a moderate increase in myogenic tone, which did not lead to significant perfusion shifts. The decrease of skin perfusion was found at the stage of regulatory violations of light-induced desynchronosis, that was accompanied by changes of both passive and active flow modulation mechanisms intensity. Skin perfusion decrease was maintained up to 21st day of the experiment and at the stage of structural defects was accompanied by a marked inhibition of the total blood flow modulation due to reduction of endothelial, myogenic, cardiac and respiratory oscillations. Conclusions. Light-induced desynchronosis causes the microcirculatory disturbances occurrence and gradually development in association with violation of neurogenic and myogenic microvascular tone, as well as endothelial dysfunction. The progression of these disorders reflects its negative influence on the circulatory system regulatory mechanisms that suggests consideration of light-induced desynchronosis as a risk factor for cardiovascular disease.

Associations of resting heart rate with endothelium-dependent vasodilation and shear rate

ABSTRACTHeart rate is an independent risk factor for cardiovascular disease and a hemodynamic factor that can modulate blood flow as it affects the frequency of shear stimuli acting on the arterial wall. However, the association between heart rate and endothelium-dependent vasodilation remains highly controversial. We determined the association between heart rate at rest and endothelium-dependent vasodilation in 98 apparently healthy adults (18–63 years). The mild and positive association between heart rate and flow-mediated dilation (FMD) was no longer significant when age and sex or baseline diameter were controlled for. The path analyses revealed that heart rate was not directly related to FMD but the association was indirectly mediated by shear rate, which was confirmed by a bias-corrected bootstrap 95% CIs (0.0157–0.1056). We concluded that even though heart rate and endothelium-dependent vasodilation were associated with shear rate, there was no independent relation between heart rate and FMD.

Differential regulation of blood flow‐induced neovascularization and mural cell recruitment by vascular endothelial growth factor and angiopoietin signalling

Key points Combining nitric oxide (NO)‐mediated increased blood flow with angiopoietin‐1–Tie2 receptor signalling induces arteriolargenesis – the formation of arterioles from capillaries – in a model of physiological angiogenesis.This NO–Tie‐mediated arteriolargenesis requires endogenous vascular endothelial growth factor (VEGF) signalling.Inhibition of VEGF signalling increases pericyte coverage in microvessels.Together these findings indicate that generation of functional neovasculature requires close titration of NO–Tie2 signalling and localized VEGF induction, suggesting that the use of exogenous VEGF expression as a therapeutic for neovascularization may not be successful. Signalling through vascular endothelial growth factor (VEGF) receptors and the tyrosine kinase with IgG and EGF domains‐2 (Tie2) receptor by angiopoietins is required in combination with blood flow for the formation of a functional vascular network. We tested the hypothesis that VEGF and angiopoietin‐1 (Ang1) contribute differentially to neovascularization induced by nitric oxide (NO)‐mediated vasodilatation, by comparing the phenotype of new microvessels in the mesentery during induction of vascular remodelling by over‐expression of endothelial nitric oxide synthase in the fat pad of the adult rat mesentery during inhibition of angiopoietin signalling with soluble Tie2 (sTie2) and VEGF signalling with soluble Fms‐like tyrosine kinase receptor‐1 (sFlt1). We found that NO‐mediated angiogenesis was blocked by inhibition of VEGF with sFlt1 (from 881 ± 98% increase in functional vessel area to 279 ± 72%) and by inhibition of angiopoietin with sTie2 (to 337 ± 67%). Exogenous angiopoietin‐1 was required to induce arteriolargenesis (8.6 ± 1.3% of vessels with recruitment of vascular smooth muscle cells; VSMCs) in the presence of enhanced flow. sTie2 and sFlt1 both inhibited VSMC recruitment (both 0%), and VEGF inhibition increased pericyte recruitment to newly formed vessels (from 27 ± 2 to 54 ± 3% pericyte ensheathment). We demonstrate that a fine balance of VEGF and angiopoietin signalling is required for the formation of a functional vascular network. Endogenous VEGF signalling prevents excess neovessel pericyte coverage, and is required for VSMC recruitment during increased nitric oxide‐mediated vasodilatation and angiopoietin signalling (NO–Tie‐mediated arteriogenesis). Therapeutic vascular remodelling paradigms may therefore require treatments that modulate blood flow to utilize endogenous VEGF, in combination with exogenous Ang1, for effective neovascularization.

Light controls cerebral blood flow in naive animals

Optogenetics is increasingly used to map brain activation using techniques that rely on functional hyperaemia, such as opto-fMRI. Here we test whether light stimulation protocols similar to those commonly used in opto-fMRI or to study neurovascular coupling modulate blood flow in mice that do not express light sensitive proteins. Combining two-photon laser scanning microscopy and ultrafast functional ultrasound imaging, we report that in the naive mouse brain, light per se causes a calcium decrease in arteriolar smooth muscle cells, leading to pronounced vasodilation, without excitation of neurons and astrocytes. This photodilation is reversible, reproducible and energy-dependent, appearing at about 0.5 mJ. These results impose careful consideration on the use of photo-activation in studies involving blood flow regulation, as well as in studies requiring prolonged and repetitive stimulations to correct cellular defects in pathological models. They also suggest that light could be used to locally increase blood flow in a controlled fashion.

How Imaging Membrane and Cell Processes Involved in Electropermeabilization Can Improve Its Development in Cell Biology and in Clinics.

Cell membranes can be transiently permeabilized under the application of electric pulses. This process, called electropermeabilization or electroporation, allows hydrophilic molecules, such as anticancer drugs and DNA, to enter into cells and tissues. The method is nowadays used in clinics to treat cancers. Vaccination and gene therapy are other fields of application of DNA electrotransfer. A description of the mechanisms can be assayed by using different complementary systems with increasing complexities (models of membranes, cells cultivated in 2D and 3D culture named spheroids, and tissues in living mice) and different microscopy tools to visualize the processes from single molecules to entire animals. Single-cell imaging experiments revealed that the uptake of molecules (nucleic acids, antitumor drugs) takes place in well-defined membrane regions and depends on their chemical and physical properties (size, charge). If small molecules freely cross the electropermeabilized membrane and have a free access to the cytoplasm, larger molecules, such as plasmid DNA, face physical barriers (plasma membrane, cytoplasm crowding, nuclear envelope) which reduce transfection efficiency and engender a complex mechanism of transfer. Gene electrotransfer indeed involves different steps that include the initial interaction with the membrane, its crossing, transport within the cytoplasm, and finally gene expression. In vivo, additional very important effects of electric pulses are present such as blood flow modifications. The full knowledge on the way molecules are transported across the electropermeabilized membranes and within tissues is mandatory to improve the efficacy and the safety of the electropermeabilization process both in cell biology and in clinics.

DIMEPHOSPHON EFFECTS ON SKIN MICROHAEMODYNAMICS

Aim . To demonstrate basic mechanisms of dimephosphon operation on skin microhaemodynamics. Materials and methods. The study of dimephosphon effect on blood microcirculation of skin in outbred male rats included registration of perfusion index, mean square deviation, variation coefficient; determination of the amplitude of blood flow oscillations in different frequency range (by laser doppler flowmetry method). Results. Dimephosphon stimulates oscillatory and non-oscillatory skin microhaemodynamic indiсes indicating the increase of peripheral tissues perfusion and blood flow modulation in microvessels due to endothelium functional activity increase, peripheral resistance decrease, increase of blood flow to the nutritive microvessel channel and venous outflow improvement. Conclusion. Vasoactive properties of dimephosphon are manifested in its ability to affect vascular and extravascular regulatory processes of blood microcirculation of skin. Microvessel endothelium and its metabolic activity associated with NO release are the most sensitive to dimephosphon effect. The ability to increase endothelium NO production is the basic mechanism of dimephosphon vasodilatory action.

Effects of thermoneutral water, cold-water and contrasting water temperature immersions on lower limb vein cross-section

Summary Objectives Immersion is often used within the framework of post-exercise recovery. Vascular effects connected to immersion are not all understood. In this study we examined the changes in common femoral vein and great saphenous vein cross-section during thermoneutral, cold, and contrasting (cold followed by hot) water immersion. Methods Ten professional handball players visited the laboratory on three occasions. At each visit, they completed a 20-minutes procedure in an upright position: 4-minutes in air (baseline) and then 16-minutes of lower limbs thermoneutral (∼35 °C), cold (∼12 °C) or contrasting (2:2 minutes [∼12 °C to ∼35 °C] ratio) water temperature immersion, in a random order. Common femoral vein and great saphenous vein cross-sections were evaluated using echo Doppler at baseline and at the end of the 16 minute immersion period under each condition. Results Common femoral vein cross-section was significantly increased after 16 minutes of immersion after each condition (+20.6% with thermoneutral, +14% with contrast and +7% with cold-water immersion, main effect for time P 0.05) during contrasting water temperature immersion and a significant decrease (−19%, P Conclusion Hydrostatic pressure, which is the same in the three immersion conditions, leads to an increase of the common femoral vein (deep venous system) cross-section no matter the water temperature. Conversely, the changes in great saphenous vein cross-section (superficial venous system) appear related to water temperature variations. This is probably related to thermoregulation mechanisms, which induce modifications in skin blood flow.

Correlation of transient adenosine release and oxygen changes in the caudate-putamen.

Adenosine is an endogenous nucleoside that modulates important physiological processes, such as vasodilation, in the central nervous system. A rapid, 2-4s, mode of adenosine signaling has been recently discovered, but the relationship between this type of adenosine and blood flow change has not been characterized. In this study, adenosine and oxygen changes were simultaneously measured using fast-scan cyclic voltammetry. Oxygen changes occur when there is an increase in local cerebral blood flow and thus are a measure of vasodilation. About 34% of adenosine transients in the rat caudate-putamen are correlated with a subsequent transient change in oxygen. The amount of oxygen was correlated with the concentration of adenosine release and larger adenosine transients (over 0.4μM) always had subsequent oxygen changes. The average duration of adenosine and oxygen transients was 3.2 and 3.5s, respectively. On average, the adenosine release starts and peaks 0.2s prior to the oxygen. The A2a antagonist, SCH442416, decreased the number of both adenosine and oxygen transient events by about 32%. However, the A1 antagonist, DPCPX, did not significantly affect simultaneous adenosine and oxygen release. The nitric oxide (NO) synthase inhibitor l-NAME also did not affect the concentration or number of adenosine and oxygen release events. These results demonstrate that both adenosine and oxygen release are modulated via A2a receptors. The correlation of transient concentrations, time delay between adenosine and oxygen peaks, and effect of A2a receptors suggests that adenosine modulates blood flow on a rapid, sub-second time scale. Read the Editorial Highlight for this article on page 10.

Modifications in blood flow observed by conjunctival angioscopy after 10 days of treatment by pentoxifylline (using 19 cases)

Modifications in blood flow observed by conjunctival angioscopy after 10 days of treatment by pentoxifylline (using 19 cases)

Low-pressure sequential compression of lower limbs enhances forearm skin blood flow.

We investigated whether forearm skin blood flow could be improved when a multilayer pulsatile inflatable suit was applied at a low pressure to the lower limbs and abdomen. We hypothesized that a non-invasive purely mechanical stimulation of the lower limbs could induce remote forearm blood flow modifications. The pulsatile suit induced a sequential compartmentalized low compression (65 mmHg), which was synchronized with each diastole of the cardiac cycle with each phase evolving centripetally (lower limbs to abdomen). Modifications of the forearm skin blood flow were continuously recorded by laser Doppler flowmetry (LDF) at baseline and during the pulsatile suit application. Endothelium-dependent and endothelium-independent vasodilations of the forearm skin microcirculation were measured by LDF in response to a local transdermal iontophoretic application of acetylcholine (ACh-test) and to hyperthermia (hyperT- test). Twenty-four healthy volunteers, 12 men and 12 women (43±14 years) were included in the study. LDF responses increased 1) under pulsatile suit (97±106%, p.