Regional Blood Flow Research Articles

Conditions for Kir-induced bistability of membrane potential in capillary endothelial cells

A simplified model for electrophysiology of endothelial cells is used to examine the conditions that can lead to bistability of membrane resting potential. The model includes the effects of inward-rectifying potassium (Kir) ion channels, whose current–voltage relationship shows an interval of negative slope and whose maximum conductance is dependent on the extracellular potassium concentration. The background current resulting from other types of channels is assumed to be linearly related to membrane potential. A method is presented for identifying the boundaries in the parameter space for the background currents of the regions of bistability. It is shown that these regions are relatively narrow and depend on extracellular potassium concentration. The results are used to define conditions leading to transitions between depolarized and hyperpolarized membrane states. These behaviors can influence the properties of conducted responses, in which changes in membrane potential are propagated along blood vessel walls. Conducted responses are important in the local regulation of blood flow in the brain and other tissues.

Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone.

Arteries and veins are lined by nonproliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis, rather than mitochondrial oxidative phosphorylation, to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells, and little is known about energy production in endothelial cells within the fully formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial respiration disrupts endothelial control of vascular tone. Basal, mechanically activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. Agonist-evoked calcium activity was also inhibited by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for mitochondria in endothelial cell energy production is independent of species, sex, or vascular bed. These data show that a mitochondrial ATP supply is necessary for calcium-dependent, nitric oxide-mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.

Regulation of cerebrovascular compliance compared with forearm vascular compliance in humans: a pharmacological study.

Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance (Ci) was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (experiment 1, phentolamine; 10 adults), cholinergic blockade (experiment 2, glycopyrrolate; 9 adults), and myogenic blockade (experiment 3, nicardipine; 14 adults). In experiment 1, phentolamine increased Ci similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular Ci (72 ± 61%) and forearm vascular Ci (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased Ci but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; P = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm.NEW & NOTEWORTHY Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.

Contrast-enhanced ultrasonography for early prediction of response of neoadjuvant chemotherapy in breast cancer.

Neoadjuvant chemotherapy (NAC) is widely accepted as a primary treatment for inoperable or locally advanced breast cancer before definitive surgery. However, not all advanced breast cancers are sensitive to NAC. Contrast-enhanced ultrasonography (CEUS) has been considered to assess tumor response to NAC as it can effectively reflect the condition of blood perfusion and lesion size. Therefore, this study aimed to evaluate the diagnostic performance of CEUS to predict early response in different regions of interest in breast tumors under NAC treatment. This prospective study included 82 patients with advanced breast cancer. Parameters of TIC (time-intensive curve) between baseline and after the first cycle of NAC were calculated for the rate of relative change (Δ), including Δpeak, ΔTTP (time to peak), ΔRBV (regional blood volume), ΔRBF (regional blood flow) and ΔMTT (mean transit time). The responders and non-responders were distinguished by the Miller-Payne Grading (MPG) system and parameters from different regions of tumors were compared in these two groups. For ROI 1(the greatest enhancement area in the central region of the tumor), there were significant differences in Δpeak1, ΔRBV1 and ΔRBF1 between responders and non-responders. For ROI 2 (the greatest enhancement area on edge of the tumor), there were significant differences in Δpeak2 and ΔRBF2 between the groups. The Δpeak1 and ΔRBF2 showed good prediction (AUC 0.798-0.820, p ≤ 0.02) after the first cycle of NAC. When the cut-off value was 0.115, the ΔRBF2 had the highest diagnostic accuracy and the maximum NPV. Quantitative TIC parameters could be effectively used to evaluate early response to NAC in advanced breast cancer.

Integrated control of coronary blood flow in exercising swine by adenosine, nitric oxide, and KATP channels.

The interplay of mechanisms regulating coronary blood flow (CBF) remains incompletely understood. Previous studies in dogs indicated that CBF regulation by KATP channels, adenosine, and nitric oxide (NO) follows a nonlinear redundancy design and fully accounted for exercise-induced coronary vasodilation. Conversely, in swine, these mechanisms appear to regulate CBF in a linear additive fashion with considerable exercise-induced vasodilation remaining when all three mechanisms are inhibited. A direct comparison between these studies is hampered by the different doses and administration routes (intravenous vs. intracoronary) of drugs inhibiting these mechanisms. Here, we investigated the role of KATP channels, adenosine, and NO in CBF regulation in swine using identical drug regimen as previously employed in dogs. Instrumented swine were exercised on a motor-driven treadmill, before and after blockade of KATP channels (glibenclamide, 50 µg/kg/min ic) and combination of inhibition of NO synthase (Nω-nitro-l-arginine, NLA, 1.5 mg/kg ic) and adenosine receptors (8-phenyltheophylline, 8PT, 5 mg/kg iv) or their combination NLA + 8PT + glibenclamide. Glibenclamide and NLA + 8PT each produced coronary vasoconstriction both at rest and during exercise, whereas the combination of NLA + 8PT + glibenclamide resulted in a small further coronary vasoconstriction compared with NLA + 8PT that was, however, less than the sum of the vasoconstriction produced by NLA + 8PT and glibenclamide, each. Thus, in contrast to previous observations in the dog, 1) the coronary vasoconstrictor effect of glibenclamide was not enhanced in the presence of NLA + 8PT and 2) the exercise-induced increase in CBF was largely maintained. These findings show profound species differences in the mechanisms controlling CBF at rest and during exercise.NEW & NOTEWORTHY The present study demonstrates important species differences in the regulation of coronary blood flow by adenosine, NO, and KATP channels at rest and during exercise. In swine, these mechanisms follow a linear additive design, as opposed to dogs which follow a nonlinear redundant design. Simultaneous blockade of all three mechanisms virtually abolished exercise-induced coronary vasodilation in dogs, whereas a substantial vasodilator reserve could still be recruited during exercise in swine.

Single Cell Approaches Reveal Perturbed Brain Vascular Molecules in Alzheimer’s Disease

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of the blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate the role of the GVU for BBB breakdown in Alzheimer’s disease (AD), the precise molecular changes contributing to its pathophysiology are unclear.MethodWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains to understand the transcriptional changes in the cells of GVU. We acquired the snRNAseq profile of 79,751 total brain cells that comprise 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge‐based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the GVU of the BBB.ResultsVascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. We validated gene expression changes using qPCR. We are in the process of evaluating these gene expression changes in antemortem blood from AD and control participants.ConclusionOur findings provide valuable information into the transcriptional changes in predicted vascular‐astrocytic partners at the GVU, highlighting insights into the molecular mechanisms of BBB breakdown in AD.

Increased Ca2+-dependent intrinsic tone and arterial stiffness in mesenteric microvessels of hypertensive pregnant rats

Preeclampsia is a pregnancy-related hypertensive disorder (HTN-Preg) with unclear mechanisms. We have shown increased vascular reactivity to extrinsic vasoconstrictors in HTN-Preg rats. Here, we test whether microvascular intrinsic tone and arterial stiffness could contribute to HTN-Preg, and examined the underlying cellular mechanisms. On gestational day 19, BP was recorded in normal pregnant (Preg) rats and Preg rats with reduced uterine perfusion pressure (RUPP), and mesenteric microvessels were mounted on a pressure myograph for measurement of intrinsic tone, simultaneous changes in [Ca2+]i (fura-2 340/380 ratio), and arterial stiffness. Arteries were incubated in Ca2+-containing and 0 Ca2+ (2 mM EGTA) Krebs, pressurized at 10 to 110 mmHg in 10 mmHg increments, and the % change in vessel diameter from initial diameter at 10 mmHg was analyzed for measurement of total (active + passive) intrinsic tone and passive intrinsic response, respectively. The passive response was then subtracted from the total intrinsic tone to determine the active myogenic tone. The strain–stress relationship was also constructed as a measure of arterial stiffness. BP was higher in RUPP vs Preg rats. In Ca2+-containing Krebs, increases in intraluminal pressure caused smaller increases in diameter and greater increases in [Ca2+]i in microvessels of RUPP vs Preg rats, suggesting increased Ca2+-dependent myogenic tone. In 0 Ca2+ Krebs, increases in pressure also caused less increases in diameter in microvessels of RUPP vs Preg rats, but with no changes in [Ca2+]i, suggesting changes in the structure and mechanics of the arterial wall. The total and passive strain–stress relationship was shifted to the left in microvessels of RUPP vs Preg rats, suggesting increased arterial wall stiffness. Histology and immunohistochemistry showed greater vascular wall thickness and collagen-I staining in RUPP vs Preg rats, supporting changes in the wall architecture and structural proteins. The increased active myogenic tone and underlying increases in Ca2+ signaling as well as the increased passive intrinsic response, arterial stiffness and collagen-I in the mesenteric microvessels could play a role in the regulation of blood flow to the splanchnic region and the increased vascular resistance and BP in HTN-Preg.

Neurovascular risk factors and dysfunction in aging and dementia

Brain function requires a finely regulated balance between the delivery of nutrients and the clearance of waste products through the blood flow.1 If the blood flow delivery does not match the dynamic requirements for oxygen and glucose imposed by neural activity, brain dysfunction and damage may ensue. The cognitive alterations caused by vascular factors (vascular cognitive impairment, VCI) and neurodegeneration (Alzheimer’s disease, AD) have traditionally been considered mechanistically distinct, but increasing evidence suggests previously unappreciated commonalities.2 Clinical-pathological studies indicate that vascular lesions aggravate the deleterious effects of AD pathology and traditional stroke risk factors, such as hypertension, are also risk factors for AD, suggesting mechanistic overlap. Furthermore, disturbances of cerebral perfusion and/or energy metabolism occur early in the clinical course of AD suggesting a pathogenic role of vascular insufficiency.3 Corroborating this clinical-epidemiological evidence, experimental data indicate that amyloid-beta, a key pathogenic factor in AD, alters the structure and function of cerebral blood vessels and associated cells (neurovascular complex), effects mediated by activation of innate immune cells leading to vascular oxidative stress and inflammation.1 On the other hand, pathological tau suppresses glutamate-dependent production of nitric oxide, which, in turn, dampens the increase in blood flow produced by synaptic activity, but also leads to neuronal network dysfunction and increased excitability.4 Aging and hypertension can also influence the production and clearance of amyloid-beta, promoting amyloid pathology. Furthermore, ApoE4 plays a critical role in the brain’s susceptibility to vascular damage or neurodegeneration.5 Injury to the neurovascular complex alters cerebral blood flow regulation, depletes vascular reserves, and reduces the brain’s repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. These observations, collectively, indicate that vascular alterations are important both in vascular and neurodegenerative dementias, and suggest novel preventive and treatment modalities for these devastating and highly prevalent conditions. Therefore, in the absence of mechanism-based approaches to counteract dementia, targeting cerebrovascular function may offer the opportunity to mitigate the public health impact of one of the most disabling human afflictions.

Cardiovascular responses to orthostasis during a simulated 3-day heatwave

Global warming has caused an increase in the frequency, duration, and intensity of summer heatwaves (HWs). Prolonged exposure to hot environments and orthostasis may cause conflicting demands of thermoregulation and blood pressure regulation on the vasomotor system, potentially contributing to cardiovascular complications and occupational heat strain. This study assessed cardiovascular and skin blood flow (SkBF) responses to orthostasis before, during and after a 3-day simulated HW. Seven male participants maintained a standard work/rest schedule for nine consecutive days split into three 3-day parts; thermoneutral pre-HW (25.4 °C), simulated HW (35.4 °C), thermoneutral post-HW. Gastrointestinal (Tgi) and skin (Tsk) temperatures, cardiovascular responses, and SkBF were monitored during 10-min supine and 10-min 60° head-up tilt (HUT). SkBF, indexed using proximal–distal skin temperature gradient (∆TskP-D), was validated using Laser-Doppler Flowmetry (LDF). The HW significantly increased heart rate, cardiac output and SkBF of the leg in supine; HUT increased SkBF of the arm and leg, and significantly affected all cardiovascular variables besides cardiac output. Significant regional differences in SkBF presented between the arm and leg in all conditions; the arm displaying vasodilation throughout, while the leg vasoconstricted in non-HW before shifting to vasodilation in the HW. Additionally, ∆TskP-D strongly correlated with LDF (r = −.78, p < 0.001). Prolonged HW exposure and orthostasis, individually, elicited significant changes in cardiovascular and SkBF variables. Additionally, varying regional blood flow responses were observed, suggesting the upper and lower vasculature receives differing vasomotor control. Combined cardiovascular alterations and shifts towards vasodilation indicate an increased challenge to industrial workers during HWs.

Cerebral blood flow regulation is not acutely altered after a typical number of headers in women footballers.

The repeated act of heading has been implicated in the link between football participation and risk of neurodegenerative disease, and acutely alters cerebrovascular outcomes in men. This study assessed whether exposure to a realistic number of headers acutely influences indices of cerebral blood flow regulation in female footballers. Nineteen female players completed a heading trial and seated control trial on two separate days. The heading trial involved six headers in 1 h (one every 10 min), with the ball traveling at 40 ± 5 km/h. Cerebrovascular reactivity to hypercapnia and hypocapnia was determined using serial breath holding and hyperventilation attempts. Dynamic cerebral autoregulation (dCA) was assessed by scrutinizing the relationship between cerebral blood flow and mean arterial blood pressure during 5 min of squat stand maneuvers at 0.05 Hz. Neurovascular coupling (NVC) was quantified as the posterior cerebral artery blood velocity response to a visual search task. These outcomes were assessed before and 1 h after the heading or control trial. No significant time by trial interaction was present for the hypercapnic (P = 0.48, = 0.05) and hypocapnic (P = 0.47, = 0.06) challenge. Similarly, no significant interaction effect was present for any metric of dCA (P > 0.12, < 0.16 for all) or NVC (P > 0.14, < 0.15 for all). The cerebral blood flow response to changes in carbon dioxide, blood pressure and a visual search task were not altered following six headers in female footballers. Further study is needed to observe whether changes are apparent after more prolonged exposure.

Prenatal exposure to alcohol: mechanisms of cerebral vascular damage and lifelong consequences.

Alcohol is a well-known teratogen, and prenatal alcohol exposure (PAE) leads to a greater incidence of many cardiovascular-related pathologies. Alcohol negatively impacts vasculogenesis and angiogenesis in the developing fetal brain, resulting in fetal alcohol spectrum disorders (FASD). Ample preclinical evidence indicates that the normal reactivity of cerebral resistance arterioles, which regulate blood flow distribution in response to metabolic demand (neurovascular coupling), is impaired by PAE. This impairment of dilation of cerebral arteries may carry implications for the susceptibility of the brain to cerebral ischemic damage well into adulthood. The focus of this review is to consolidate findings from studies examining the influence of PAE on vascular development, give insights into relevant pathological mechanisms at the vascular level, evaluate the risks of ethanol-driven alterations of cerebrovascular reactivity, and revisit different preventive interventions that may have promise in reversing vascular changes in preclinical FASD models.

Apathy in depression: An arterial spin labeling perfusion MRI study

IntroductionApathy, as defined as a deficit in goal-directed behaviors, is a critical clinical dimension in depression associated with chronic impairment. Little is known about its cerebral perfusion specificities in depression. To explore neurovascular mechanisms underpinning apathy in depression by pseudo-continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI). MethodsPerfusion imaging analysis was performed on 90 depressed patients included in a prospective study between November 2014 and February 2017. Imaging data included anatomical 3D T1-weighted and perfusion pCASL sequences. A multiple regression analysis relating the quantified cerebral blood flow (CBF) in different regions of interest defined from the FreeSurfer atlas, to the Apathy Evaluation Scale (AES) total score was conducted. ResultsAfter confound adjustment (demographics, disease and clinical characteristics) and correction for multiple comparisons, we observed a strong negative relationship between the CBF in the left anterior cingulate cortex (ACC) and the AES score (standardized beta = −0.74, corrected p value = 0.0008). ConclusionOur results emphasized the left ACC as a key region involved in apathy severity in a population of depressed participants. Perfusion correlates of apathy in depression evidenced in this study may contribute to characterize different phenotypes of depression.

Combination of indirect revascularization and endothelial progenitor cell transplantation improved cerebral perfusion and ameliorated tauopathy in a rat model of bilateral ICA ligation

ObjectiveEndothelial progenitor cells (EPCs) contribute to the recovery of neurological function after ischemic stroke. Indirect revascularization has exhibited promising effects in the treatment of cerebral ischemia related to moyamoya disease and intracranial atherosclerotic disease. The role of EPCs in augmenting the revascularization effect is not clear. In this study, we investigated the therapeutic effects of indirect revascularization combined with EPC transplantation in rats with chronic cerebral ischemia.MethodsChronic cerebral ischemia was induced by bilateral internal carotid artery ligation (BICAL) in rats, and indirect revascularization by encephalo-myo-synangiosis (EMS) was performed 1 week later. During the EMS procedure, intramuscular injection of EPCs and the addition of stromal cell-derived factor 1 (SDF-1), and AMD3100, an SDF-1 inhibitor, were undertaken, respectively, to investigate their effects on indirect revascularization. Two weeks later, the cortical microcirculation, neuronal damage, and functional outcome were evaluated according to the microvasculature density and partial pressure of brain tissue oxygen (PbtO2), regional blood flow, expression of phosphorylated Tau (pTau), TUNEL staining and the rotarod performance test, respectively.ResultsThe cortical microcirculation, according to PbtO2 and regional blood flow, was impaired 3 weeks after BICAL. These impairments were improved by the EMS procedure. The regional blood flow was further increased by the addition of SDF-1 and decreased by the addition of AMD3100. Intramuscular injection of EPCs further increased the regional blood flow as compared with the EMS group. The rotarod test results showed that the functional outcome was best in the EMS combined with EPC injection group. Western blot analysis showed that the EMS combined with EPC treatment group had significantly decreased expressions of phosphorylated Tau and phosphorylated glycogen synthase kinase 3 beta (Y216 of GSK-3β). pTau and TUNEL-positive cells were markedly increased at 3 weeks after BICAL induction. Furthermore, the groups treated with EMS combined with SDF-1 or EPCs exhibited marked decreases in the pTau expression and TUNEL-positive cells, whereas AMD3100 treatment increased TUNEL-positive cells.ConclusionThe results of this study suggested that indirect revascularization ameliorated the cerebral ischemic changes. EPCs played a key role in augmenting the effect of indirect revascularization in the treatment of chronic cerebral ischemia.

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

Prion diseases are neurodegenerative disorders with long asymptomatic incubation periods, followed by a rapid progression of cognitive and functional decline culminating in death. The complexity of intercellular interactions in the brain is challenging to unravel and the basis of disease pathobiology remains poorly understood. In this study, we employed single cell RNA sequencing (scRNAseq) to produce an atlas of 147,536 single cell transcriptomes from cortex and hippocampus of mice infected with prions and showing clinical signs. We identified transcriptionally distinct populations and sub-populations of all the major brain cell-types. Disease-related transcription was highly specific to not only overarching cell-types, but also to sub-populations of glia and neurons. Most striking was an apparent decrease in relative frequency of astrocytes expressing genes that are required for brain homeostasis such as lipid synthesis, glutamate clearance, synaptic modulation and regulation of blood flow. Additionally, we described a spectrum of microglial activation states that suggest delineation of phagocytic and neuroinflammatory functions in different cell subsets. Differential responses of immature and mature neuron populations were also observed, alongside abnormal hippocampal neurogenesis. Our scRNAseq library provides a new layer of knowledge on single cell gene expression in prion disease, and is a basis for a more detailed understanding of cellular interplay that leads to neurodegeneration.

Abstract 10128: Recombinant Human Placental Growth Factor-2 Treatment in Porcine Ischemic Cardiomyopathy

Background: Placental growth factor (PlGF)-2 induces neovascularization and improves myocardial function in atherosclerotic rodent myocardial ischemia models without stimulating plaque angiogenesis. This promising therapeutic profile of PlGF-2 warrants a double blind, randomized, and placebo-controlled feasibility and efficacy study in a large animal model, representative of human disease. Methods: We induced myocardial infarction (MI) in domestic pigs using a 75 min balloon occlusion of the mid-LAD followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF&lt;40%) to continuous IV infusion of 5, 15, 45 μg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated treatment effect 8 w after MI using comprehensive MRI analysis of LV function and structure and performed postmortem histological analyses of LV vascularization and fibrotic remodeling. Results: In the pilot study (3 pigs/dose), PIGF plasma concentrations showed stable and sustained dose-dependent increases for 28 days without organ-specific side effects or systemic toxicity. Myocardial Ischemia/reperfusion induced LV dysfunction at 4 w (infarct size, 16±4 % of LV mass, n=42; LVEF, 34±4 %, range 19%-40%). In the dose escalation study using 5 (n=10), 15 or 45 μg/kg/day PlGF (n=11 per group), global LV function, and regional myocardial blood flow at rest or during stress, and infarct size did not differ between CON (n=10) and PlGF (Figure 1). Capillary densities and extent of LV interstitial fibrosis in infarct core and border zone were comparable between CON and PlGF. Conclusions: In this blinded randomized controlled trial, rhPIGF-2 did not improve global cardiac function in a porcine model of chronic ischemic cardiomyopathy, and failed to recapitulate therapeutic neovascularization reported in rodents. Our data emphasize the critical need for robust double blind, placebo controlled trials in representative large animal models before clinical translation.

Mechanisms that underlie blood flow regulation at rest and during exercise.

The cardiovascular system must distribute oxygen and nutrients to the body while maintaining appropriate blood pressure. This is achieved through a combination of central and peripheral mechanisms that influence cardiac output and vasomotor tone throughout the vascular system. Furthermore, the capability to preferentially direct blood to tissues with increased metabolic demand (i.e., active hyperemia) is crucial to exercise tolerance. However, the interaction between these systems is difficult to understand without real-life examples. Fortunately, monitoring blood flow, blood pressure, and heart rate during a series of laboratory protocols will allow students to partition the contributions of these central and peripheral factors. The three protocols include 1) reactive hyperemia in the forearm, 2) small muscle mass handgrip exercise, and 3) large muscle mass cycling exercise. In addition to providing a detailed description of the required equipment, specific protocols, and expected outcomes, this report also reviews some of the common student misconceptions that are associated with the observed physiological responses.NEW & NOTEWORTHY Blood flow regulation during exercise is a complicated process that involves many overlapping mechanisms. This laboratory will help students better understand how the body regulates blood flow to the active muscles using three separate protocols: 1) reactive hyperemia, 2) small muscle mass exercise, and 3) large muscle mass exercise.

Hemodynamic analysis of a curved artery based on microcirculation boundary.

Microcirculation plays a key role in regulating blood flow but is not considered in previous research of hemodynamics. A curved artery model is established to study its hemodynamic characteristics based on microcirculation boundary. The hemodynamic model of a curved artery is constructed and simulated by computational fluid dynamics. The curved artery model is simulated by fluid-structure interaction. At the same time, a porous medium is used to simulate microcirculation as the outlet boundary. The distribution characteristics of the blood flow velocity, the pressure and the wall shear stress in different sections at different time of the cardiac cycle are obtained. The results show that the velocities in curved arteries decrease and the pressures gradually increase. The blood flow velocity waveform and value are affected and they are sensitive to the microcirculation boundary. However, the pressure value is only affected by the microcirculation function. This work is useful for researchers to deeply understand the hemodynamic characteristics of curved arteries. There is important clinical significance to analyze the pathogenesis of cardiovascular disease considering microcirculation function and its coupling effect.

Patient-Specific Computational Modeling of Different Cannulation Strategies for Extracorporeal Membrane Oxygenation.

Institution of extracorporeal membrane oxygenation (ECMO) results in unique blood flow characteristics to the end-organ vascular beds. We studied the interplay between cardiac-driven and extracorporeal membrane oxygenation (ECMO)-driven flow to vascular beds in different ECMO configurations using a patient-specific computational fluid dynamics (CFD) analysis. A computational ECMO model (femoral artery cannulation [FAC]) was constructed using patient-specific imaging and hemodynamic data. Following model calibration, we augmented the 3D geometrical model to represent alternative ECMO configurations (ascending aorta cannulation [AAC] and subclavian artery cannulation [SAC]). We performed CFD analyses, including a novel virtual color-dye analysis to compare global and regional blood flow and pressure characteristics as well as contributions of cardiac and ECMO-derived flow to the various vascular beds. Flow waveforms at all the aortic branch vessels were pulsatile, despite low cardiac output and predominant nonpulsatile ECMO-driven hemodynamics. Virtual color-dye analysis revealed differential contribution of cardiac and ECMO-derived flow to the end-organ vascular beds in the FAC model, while this was more evenly distributed in the AAC and SAC models. While global hemodynamics were relatively similar between various ECMO configurations, several distinct hemodynamic indices, in particular wall shear stress and oscillatory shear patterns, as well as differential contribution of ECMO-derived flow to various vascular beds, showed remarkable differences. The clinical impact of this study highlighting the relevance of CFD modeling in assessment of complex hemodynamics in ECMO warrants further evaluation.

Effect of wearing and washing temperature on the performance of compression socks

Compression socks regulate blood flow in venous systems and are used for therapeutic purposes. The present study, it was aimed to analyse the influence of multiple levels of wearing and washing temperature on compression pressure. 9 pieces of compression socks samples with 3 different combinations (with different polyamide/ elastane body and inlaid yarn) were developed using compression socks knitting machine with a 1×1 laid in, 1×1 knit-miss structure. After the production of the samples, to simulate the “wearing and washing effect” a test protocol was designed. Compression pressure values were measured by using MST Professional II Medical Stocking Tester in different phases and results were evaluated statistically. The results show that when compression socks are worn for 15 days and washed 5 times, their compression pressure and graduation values change. After wearing compression socks on wooden leg pressure values shows a slight decrease due to a long period of stretching. In addition, after wearing and washing cycles it is seen that the pressure values increase as the washing temperature increases. 50 ̊C results show the highest increase at compression pressure. Statistical results show a correlation between temperature and compression pressure. Many researches were carried out on the production factors of compression socks, however, there are very few research studies on the usage performance of socks. The study contains results for both the literature and the producers/end users

Toward a granular molecular-anatomic map of the blood vasculature – single-cell RNA sequencing makes the leap

Single-cell RNA sequencing (scRNAseq) marks the birth of a new era in physiology and medicine. Within foreseeable future, we will know exactly what genes are expressed - and at what levels - in all the different cell types and subtypes that make up our bodies. We will also learn how a particular cell state, whether it occurs during development, tissue repair, or disease, reflects precise changes in gene expression. While profoundly impacting all areas of life science, scRNAseq may lead to a particular leap in vascular biology research. Blood vessels pervade and fulfill essential functions in all organs, but the functions differ. Innumerable organ-specific vascular adaptations and specializations are required. These, in turn, are dictated by differential gene expression by the two principal cellular building blocks of blood vessels: endothelial cells and mural cells. An organotypic vasculature is essential for functions as diverse as thinking, gas exchange, urine excretion, and xenobiotic detoxification in the brain, lung, kidney, and liver, respectively. In addition to the organotypicity, vascular cells also differ along the vascular arterio-venous axis, referred to as zonation, differences that are essential for the regulation of blood pressure and flow. Moreover, gene expression-based molecular changes dictate states of cellular activity, necessary for angiogenesis, vascular permeability, and immune cell trafficking, i.e. functions necessary for development, inflammation, and repair. These different levels of cellular heterogeneity create a nearly infinite phenotypic diversity among vascular cells. In this review, I summarize and exemplify what scRNAseq has brought to the picture in just a few years and point out where it will take us.