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Purpose: To evaluate the influence of warm-up exercise intensity and subsequent recovery on intense endurance performance, selected blood variables, and the oxygen-uptake (VO2) response. Methods: Twelve highly trained male cyclists (VO2max 72.4 ± 8.0 mL • min–1 • kg–1, incremental-test peak power output (iPPO) 432 ± 31 W; mean ± SD) performed 3 warm-up strategies lasting 20 min before a 4-min maximal-performance test (PT). Strategies consisted of moderate-intensity exercise (50%iPPO) followed by 6 min of recovery (MOD6) or progressive high-intensity exercise (10–100%iPPO and 2 × 20-s sprints) followed by recovery for 6 min (HI6) or 20 min (HI20). Results: Before PT venous pH was lower (P < .001) in HI6 (7.27 ± 0.05) than in HI20 (7.34 ± 0.04) and MOD6 (7.35 ± 0.03). At the same time, differences (P < .001) existed for venous lactate in HI6 (8.2 ± 2.0 mmol/L), HI20 (5.1 ± 1.7 mmol/L), and MOD6 (1.4 ± 0.4 mmol/L), as well as for venous bicarbonate in HI6 (19.3 ± 2.6 mmol/L), HI20 (22.6 ± 2.3 mmol/L), and MOD6 (26.0 ± 1.4 mmol/L). Mean power in PT in HI6 (402 ± 38 W) tended to be lower (P = .11) than in HI20 (409 ± 34 W) and was lower (P = .007) than in MOD6 (416 ± 32 W). Total VO2 (15–120 s in PT) was higher in HI6 (8.18 ± 0.86 L) than in HI20 (7.85 ± 0.82 L, P = .008) and MOD6 (7.90 ± 0.74 L, P = .012). Conclusions: Warm-up exercise including race-pace and sprint intervals combined with short recovery can reduce subsequent performance in a 4-min maximal test in highly trained cyclists. Thus, a reduced time at high exercise intensity, a reduced intensity in the warm-up, or an extension of the recovery period after an intense warm-up is advocated. [ABSTRACT FROM AUTHOR]

Pancreatic cancers, both adenocarcinomas and endocrine tumors are characterized by varying levels of aberrant angiogenesis and fibrotic microenvironment. The difficulty to deliver drugs and treat the disease has been attributed in part to the vascular architecture and tissue/ECM density. Here we present longitudinal three‐dimensional intravital imaging of vascular and tumor microenvironment remodeling in spontaneous transgenic tumors (RIP1‐Tag2 insulinomas) and orthotopically injected tumors (KPC adenocarcinomas). Analysis of the data acquired in insulinomas revealed major differences in tumor blood vessel branching, fraction volume, number of branch points segments, vessel straightness and length compared to the normal tissue. The aggressive adenocarcinoma presented widespread peritumoral vascular remodeling and heterogeneous vascular distribution. Longitudinal imaging was used to acquire sequential vascular remodeling data during tumor progression. This work demonstrates the potential for using a pancreatic intravital imaging window for direct visualization of the tumor heterogenic microenvironments during tumor progression. What's new? In pancreatic cancer, the difficulty to deliver therapeutic drugs has been attributed partly to the tumor vascular architecture and tissue/extracellular matrix density. Here, the authors present a novel method for longitudinal intravital imaging of preclinical models of pancreatic cancer that enables direct visualization of blood vessels remodeling and quantification of vascular parameters. The results provide information on blood vessel diameter, volume, length, branching, and straightness in spontaneous transgenic tumors and on vessel volume and heterogeneity in syngeneic fluorescent orthotopically‐injected adenocarcinomas. The work provides new monitoring tools together with quantifiable architectural features and potential biomarkers of vascular abnormalities in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Introduction: The study evaluated the role of lifelong physical activity for leg vascular function in postmenopausal women (61 ± 1 yr). Method: The study design was cross-sectional with three different groups based on self-reported physical activity level with regard to intensity and volume over the past decade: inactive (n = 14), moderately active (n = 12), and very active (n = 15). Endothelial-dependent and smooth muscle-dependent leg vascular function were assessed by ultrasound Doppler measurements of the femoral artery during infusion of acetylcholine (Ach), the nitric oxide (NO) donor sodium nitroprusside and the prostacyclin analog epoprostenol. Thigh muscle biopsies, arterial and venous plasma samples were obtained for assessment of vasodilator systems. Results: The very active group was found to have 76% greater responsiveness to Ach compared with the sedentary group accompanied by 200% higher prostacyclin synthesis during Ach infusion. Smooth muscle cell responsiveness to sodium nitroprusside and epoprostenol was not different between groups. The protein amount of endothelial NO synthase and endogenous antioxidant enzymes in muscle tissue was higher in the very active than the inactive group. The moderately active group had a similar endothelial and smooth muscle cell responsiveness as the inactive group. A secondary comparison with a smaller group (n = 5) of habitually active young (24 ± 2 yr) women indicated that smooth muscle cell responsiveness and endothelial responsiveness are affected by age per se. Conclusions: This study shows that leg vascular function and the potential to form prostacyclin and NO in late postmenopausal women, is influenced by the extent of lifelong physical activity. [ABSTRACT FROM AUTHOR]

Context Berries are a source of polyphenols with recognized health-promoting activities. Several studies suggest that consumption of berries may improve vascular function. Objective The aim of this systematic review is to provide evidence of short- and long-term benefits of berries on outcomes of vascular function. Data Sources Human intervention studies were collected from PubMed and Scopus databases. Study Selection Studies were eligible if they investigated the effects of acute or chronic berry consumption on one or more markers of vascular function in humans and provided a characterization of the berry polyphenolic content. Only randomized controlled trials were included, and studies were excluded if berries were combined with other foods. Data Extraction After selection, 22 randomized controlled trials were included and analyzed, most of which were performed in healthy individuals or patients with cardiovascular risk factors. Results The overall results seem to suggest a protective role of berries in vascular function, likely dependent on the time of exposure, the type and dose of berry, and the biomarkers analyzed. Flow-mediated dilation and reactive hyperemia index (markers of vascular reactivity) improved following short-term interventions, while pulse wave velocity and augmentation index (markers of arterial stiffness) improved only after medium- to long-term intervention. Conclusions Current evidence suggests that berries, at physiological relevant doses, may have a role in the modulation of vascular function and stiffness. High-quality human intervention trials are encouraged in order to strengthen these findings and to better elucidate the mechanisms involved in such modulation. [ABSTRACT FROM AUTHOR]

Introduction: The effects of magnesium (Mg) supplementation on vascular function have been evaluated in some randomized controlled trials (RCT) but their results are conflicting. Aim: A systematic review and meta-analysis were conducted to summarize the effects of oral Mg supplementation on vascular function in RCT. Methods: The databases MEDLINE (PubMed), Embase, Web of Science and Cochrane Library were accessed from inception to May 27, 2019. Intergroup differences (treatment vs. control group) related to changes in flow-mediated dilation (FMD) and pulse wave velocity (PWV), expressed as mean and standard deviation, were used to evaluate the effect of Mg supplementation on these outcomes. The results of the meta-analysis were expressed using a random-effects model. The heterogeneity between studies was evaluated using the I2 statistic. Results: The oral supplementation of Mg had no significant effect on FMD (mean difference 2.13; 95% CI − 0.56, 4.82; p = 0.12) and PWV (mean difference − 0.54, 95% CI − 1.45, 0.36, p = 0.24). Heterogeneity for both outcomes (FMD and PWV) was high (I2 = 99%, p < 0.001). However, in subgroup analyses, oral Mg significantly improved FMD in studies longer than 6 months, in unhealthy subjects, in individuals older than 50 years, or in those with body mass index (BMI) ≥ 25 kg/m2. The reduced number of RCT and the heterogeneity among them were the main limitations. Conclusions: This meta-analysis suggest that oral Mg supplementation may improve endothelial function when conducted at least for 6 months and in unhealthy, overweight or older individuals. Registration number: PROSPERO CRD42019111462. [ABSTRACT FROM AUTHOR]

This study investigated the effect of endurance training and regular post-exercise cold water immersion on changes in microvascular function. Nine males performed 3 sessions∙wk-1 of endurance training for 4 weeks. Following each session, participants immersed one leg in a cold water bath (10°C; COLD) for 15 min while the contra-lateral leg served as control (CON). Before and after training, microvascular function of the gastrocnemius was assessed using near-infrared spectroscopy, where 5 min of popliteal artery occlusion was applied and monitored for 3 min upon cuff release. Changes in Hbdiff (oxyhemoglobin – deoxyhemoglobin) amplitude (O-AMP), area under curve (O-AUC) and estimated muscle oxygen consumption (mVO2) were determined during occlusion, while the reperfusion rate (R-RATE), reperfusion amplitude (R-AMP) and hyperemic response (HYP) were determined following cuff release. Training increased O-AMP (p=0.010), O-AUC (p=0.011), mVO2 (p=0.013), R-AMP (p=0.004) and HYP (p=0.057). Significant time (p=0.024) and condition (p=0.026) effects were observed for R-RATE, where the increase in COLD was greater compared with CON (p=0.026). In conclusion, R-RATE following training was significantly higher in COLD compared with CON, providing some evidence for enhanced microvascular adaptations following regular cold water immersion. [ABSTRACT FROM AUTHOR]

Aims: To characterize and contrast human sensory and vascular changes produced by topical application of the algesic chemical capsaicin to the glabrous lips and tongue. Methods: Applications of 1% capsaicin or vehicle cream to the glabrous lips and tongue were randomized between two two-trial sessions. The capsaicin trial followed the vehicle trial for each session. Before and 5, 15, and 30 minutes after capsaicin or vehicle cream application, six parameters were recorded from the glabrous lips or the tongue dorsum: (1) burning pain intensity, as measured on a visual analog scale; (2) burning pain area, as indicated by subjects on an orofacial drawing; (3) mechanical sensitivity, as measured by a von Frey filament; (4) visual flare; (5) blood flow and temperature, as measured by laser-Doppler imaging and thermography, respectively; and (6) areas of increased temperature (hot spots), as calculated by a digital tracer from the thermographs. Data were analyzed by ANOVAs and Pearson's correlations. Results: Compared to vehicle application, capsaicin elicited burning pain, increases in blood flow and temperature, but no change in mechanical sensitivity in the glabrous lips or tongue. Greater increases in blood flow and temperature paralleled more intense burning pain and larger areas of perceived pain for the lips compared to the tongue. The location of distinct areas of increased temperature within the orofacial area differed between the capsaicin-lip and capsaicin-tongue trials. Conclusion: The several differences between these responses to noxious stimulation of the glabrous lips and tongue may have implications for examinations of orofacial somatosensory functions. [ABSTRACT FROM AUTHOR]

Passive exercise/movement has a long history in both medicine and physiology. Early clinical applications of passive exercise/movement utilized pneumatic and direct limb compression to stimulate the vasculature and evoke changes in blood flow to avoid complications brought about by stasis and vascular disease. Over the last 50 years, passive exercise/movement has continued to progress and has provided physiologists with a reductionist approach to mechanistically examine the cardiorespiratory, hyperemic, and afferent responses to movement without the confounding influence of metabolism that accompanies active exercise. This review, in addition to providing an historical perspective, focuses on the recent advancements utilizing passive leg movement, and how the hyperemic response at the onset of this passive movement has evolved from a method to evaluate the central and peripheral regulation of blood flow during exercise to an innovative and promising tool to assess vascular function. As an assessment of vascular function, passive leg movement is relatively simple to perform and provides a nitric oxide-dependent evaluation of endothelial function across the lifespan that is sensitive to changes in activity/fitness and disease state (heart failure, peripheral artery disease, sepsis). The continual refinement and characterization of passive leg movement are aimed at improving our understanding of blood flow regulation and the development of a clinically ready approach to predict and monitor the progression of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Healthy and functional endothelial cells play important roles in maintaining vascular homeostasis, whereas endothelial dysfunction initiates and exacerbates vascular disease progression. Interventional studies with dietary fatty acids have shown that these molecules have varying effects on vascular function. It is hypothesized that the actions of dietary fatty acids on vascular function may be mediated in part through endothelial cells. This review summarizes the results of studies that have examined the acute and chronic effects of dietary fatty acids on endothelial function and vascular properties in humans, as well as the potential mechanisms by which n-3 polyunsaturated fatty acids regulate endothelial function. Altogether, this article provides an extensive review of how fatty acids contribute to vascular function through their ability to modulate endothelial cells and discusses relationships between dietary fatty acids and endothelial cells in the context of vascular dysfunction. [ABSTRACT FROM AUTHOR]

Background Anthocyanin-rich blueberry intake is associated with reduced type 2 diabetes and cardiovascular disease (CVD) risk in prospective studies, although long-term randomized controlled trials (RCTs) have not been conducted in at-risk populations. Objective In the longest-duration RCT to date, we examined the effect of 6-mo blueberry intake on insulin resistance and cardiometabolic function in metabolic syndrome. Methods A double-blind, parallel RCT (n  = 115; age 63 ± 7 y; 68% male; body mass index 31.2 ± 3.0 kg/m2) was conducted, which fed 2 dietarily achievable blueberry intakes [equivalent to 1/2 and 1 cup/d (75/150 g)] compared with matched placebo. Insulin resistance was assessed via the homeostasis model assessment of insulin resistance (primary endpoint) and confirmed by [6-6-2H2]-glucose-labeled, 2-step hyperinsulinemic clamp (n  = 20). Clinically relevant cardiometabolic endpoints [including flow-mediated dilatation, augmentation index, lipoprotein status (by nuclear magnetic resonance spectroscopy), and nitric oxide (NO)-related metabolite assay] and anthocyanin metabolism were assessed. Results A daily intake of 1 cup of blueberries improved endothelial function (flow-mediated dilatation: +1.45%; 95% CI: 0.83%, 2.1%; P  = 0.003), systemic arterial stiffness (augmentation index: –2.24%; 95% CI: –3.97%, –0.61%; P  = 0.04) and attenuated cyclic guanosine monophosphate concentrations. In statin nonusers (n  = 71), elevated high-density lipoprotein cholesterol (+0.08 mmol/L; P  = 0.03), high-density lipoprotein particle density (+0.48 n, ×10–6; P  = 0.002) and apolipoprotein A-I (+0.05 g/L; P  = 0.01) concentrations were observed following the 1-cup/d intervention. Treatment compliance was 94.1% (wrapper returns) and total concentrations of anthocyanin-derived phenolic acid metabolites significantly increased, dose-dependently, in serum and 24-h urine (P  < 0.01 and P  < 0.001, respectively). Insulin resistance, pulse wave velocity, blood pressure, NO, and overall plasma thiol status were unaffected. Likewise, a half cup per day had no effect on any biomarkers. Conclusions Despite insulin resistance remaining unchanged we show, to our knowledge, the first sustained improvements in vascular function, lipid status, and underlying NO bioactivity following 1 cup blueberries/d. With effect sizes predictive of 12–15% reductions in CVD risk, blueberries should be included in dietary strategies to reduce individual and population CVD risk. This study was registered at clinicaltrials.gov as NCT02035592. [ABSTRACT FROM AUTHOR]

Purpose. To evaluate the changes in retinal vessel density and thickness after small incision lenticule extraction (SMILE) with optical coherence tomography angiography (OCTA) in myopic patients. Methods. In this prospective study, SMILE surgeries were done in 46 eyes of 24 patients with spherical equivalent (SE) more than −6.0 diopters (D). Retinal vessel density and thickness at the macula and optic nerve were recorded with OCTA before and 1 day, 2 weeks, and 1 month after surgery. Intraocular pressure (IOP), uncorrected distance visual acuity (UDVA), and refraction were taken at the same time. Results. The superficial retinal vessel density and deep foveal retinal vessel density 1 day after surgery were less than those before surgery; however, the changes at any timepoints were not statistically significant (p=0.2736 and p=0.1590, respectively). Both the superficial vessel density and deep vessel density at the parafoveal and perifoveal regions decreased significantly 1 day postoperatively (all p<0.05) and then returned to the preoperative level at 2 weeks and stabilized thereafter. There were no significant changes in any of the 4 vessel densities in the area of peripapillary before and 1 day, 2 weeks, and 1 month after surgery (p=0.3345). No statistically significant differences between preoperative and postoperative retinal thickness were detected for the area of macula and optic nerve (all p>0.5). Conclusions. The vessel density at the parafoveal and perifoveal regions decreased at 1 day after SMILE with no effect on the visual acuity and relieved within 2 weeks. Decreased ocular blood flow in response to the spike in IOP may account for such changes. [ABSTRACT FROM AUTHOR]

Microvascular function is reduced with age, disease, and inactivity. Exercise is well known to improve vascular health and has the potential to improve microvascular function in aging and disease. Purpose: The study aimed to assess changes in peripheral microvascular function in sedentary older adults after aerobic exercise training. Methods: Twenty-three sedentary older adults (67 ± 5 yr, body mass index = 29 ± 5, mean ± SD) successfully completed a randomized 12-wk graded treadmill walking intervention. The exercise group (EX) performed 40 min of uphill walking 4 d·wk−1 at 70% heart rate reserve. The control group (CON) maintained a sedentary lifestyle for 12 wk. Blood oxygen level–dependent (BOLD) responses of the soleus measured by magnetic resonance imaging were used to evaluate microvascular function; brief (1 s) maximal plantarflexion contractions were performed. Separately, blood flow in the popliteal artery was measured by ultrasound after brief contraction. Phosphorus magnetic resonance spectroscopy of the calf was used to examine muscle oxidative capacity, and whole-body peak oxygen consumption (V˙O2peak) was used to confirm training-induced cardiorespiratory adaptations. Results: Peak postcontraction BOLD response increased by 33% in EX (PRE, 3.3% ± 1.0%; POST, 4.4% ± 1.4%) compared with CON (PRE, 3.0% ± 1.3%; POST, 3.2% ± 1.5%), P < 0.05. EX with hypertension tended to show a blunted peak BOLD increase (n = 6, 15%) compared with EX normotensive (n = 7, 50%), P = 0.056. Peak postcontraction blood flow increased by 39% in EX (PRE, 217 ± 88 mL·min−1; POST, 302 ± 167 mL·min−1) compared with CON (PRE, 188 ± 54 mL·min−1; POST, 184 ± 44 mL·min−1), P < 0.05. EX muscle oxidative capacity (k PCr) improved by 40% (PRE, 1.60 ± 0.57 min−1; POST, 2.25 ± 0.80 min−1) compared with CON (PRE, 1.69 ± 0.28 min−1; POST, 1.76 ± 0.52 min−1), P < 0.05. V˙O2peak increased by 9% for EX (PRE, 19.0 ± 3.1 mL·kg−1·min−1; POST, 20.8 ± 2.9 mL·kg−1·min−1) compared with a 7% loss in CON (PRE, 21.9 ± 3.6 mL·kg−1·min−1; POST, 20.4 ± 3.5 mL·kg−1·min−1), P < 0.05. Conclusion: Moderate aerobic exercise significantly improved microvascular function of the leg in older adults. [ABSTRACT FROM AUTHOR]

Traumatic brain injury is a devastating cause of death and disability. Although injury of brain tissue is of primary interest in head trauma, nearly all significant cases include damage of the cerebral blood vessels. Because vessels are critical to the maintenance of the healthy brain, any injury or dysfunction of the vasculature puts neural tissue at risk. It is well known that these vessels commonly tear and bleed as an immediate consequence of traumatic brain injury. It follows that other vessels experience deformations that are significant though not severe enough to produce bleeding. Recent data show that such subfailure deformations damage the microstructure of the cerebral vessels, altering both their structure and function. Little is known about the prognosis of these injured vessels and their potential contribution to disease development. The objective of this review is to describe the current state of knowledge on the mechanics of cerebral vessels during head trauma and how they respond to the applied loads. Further research on these topics will clarify the role of blood vessels in the progression of traumatic brain injury and is expected to provide insight into improved strategies for treatment of the disease. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcer (DFU) is a problem worldwide, and prevention is crucial. We hypothesized that the inability of the skin to respond to pressure is involved in DFU pathogenesis and could be an important predictive factor to take into account. We included 29 patients with DFU and 30 patients with type 2 diabetes without DFU. Neuropathy and skin blood flow at rest were assessed in response to acetylcholine, sodium nitroprusside, local heating (42°C), and to nonnoxious locally applied pressure. Results were compared with those obtained from 10 healthy age-matched control subjects. Vasodilatation in response to pressure was significantly impaired in both groups with diabetes compared with healthy subjects. The vasodilator capacity to pressure was significantly lower in patients with DFU compared with those without DFU, despite the absence of significant difference in cutaneous pressure perception threshold and vascular reactivity to acetylcholine, sodium nitroprusside, and heat. This pronounced alteration of neurovascular response to pressure in patients with DFU is a good marker of skin vulnerability and could be used to better predict individuals at risk. [ABSTRACT FROM AUTHOR]

Highlights • The principle of uniform flow may explain the morphology of microvascular networks. • A gradient descent algorithm is devised to find networks that optimize general combinations of functions and constraints. • On model capillary beds, uniform flow networks provably have the same flows as uniform conductance networks. • A theoretical zebrafish trunk network that optimizes uniform flow quantitatively matches real zebrafish microvascular data. • Networks constrained by material and transport costs undergo a phase transition if the relative burden of the two is varied. Abstract Within animals, oxygen exchange occurs within vascular transport networks containing potentially billions of microvessels that are distributed throughout the body. By comparison, large blood vessels are theorized to minimize transport costs, leading to tree-like networks that satisfy Murray's law. We know very little about the principles underlying the organization of healthy micro-vascular networks. Indeed capillary networks must also perfuse tissues with oxygen, and efficient perfusion may be incompatible with minimization of transport costs. While networks that minimize transport costs have been well-studied, other optimization principles have received much less scrutiny. In this work we derive the morphology of networks that uniformize blood flow distribution, inspired by the zebrafish trunk micro-vascular network. To find uniform flow networks, we devise a gradient descent algorithm able to optimize arbitrary differentiable objective functions on transport networks, while exactly respecting arbitrary differentiable constraint functions. We prove that in a class of networks that we call stackable, which includes a model capillary bed, the uniform flow network will have the same flow as a uniform conductance network, i.e., in which all edges have the same conductance. This result agrees with uniform flow capillary bed network found by the algorithm. We also show that the uniform flow completely explains the observed radii within the zebrafish trunk vasculature. In addition to deriving new results on optimization of uniform flow in micro-vascular networks, our algorithm provides a general method for testing hypotheses about possible optimization principles underlying real microvascular networks, including exposing tradeoffs between flow uniformity and transport cost. [ABSTRACT FROM AUTHOR]

Background: The most important determinant of long-term survival in patients with idiopathic pulmonary fibrosis is the right ventricular (RV) adaptation to the increased pulmonary vascular resistance. Our aim was to explore RV contractile reserve during stress echocardiography in early-stage IPF.Methods: Fifty early-stage patients with IPF and 50 healthy control patients underwent rest and stress echocardiography, including RV two-dimensional speckle tracking echocardiography. At peak exertion, blood gas analysis and spirometry were also assessed.Results: At rest, RV diameters were mildly increased in IPF; however, although RV conventional systolic function indexes were similar between the IPF and control groups, RV global longitudinal strain and RV lateral wall longitudinal strain (LWLS) were significantly reduced in the IPF cohort. During physical exercise, patients with IPF showed a reduced exercise tolerance with lower maximal workload (P < .01), level of oxygen saturation (P < .001), and peak heart rate (P < .01). Systolic and diastolic BP values were similar in both groups. Systolic pulmonary artery pressure (PAPs) increase (ΔPAPs) during exertion was higher in IPF vs healthy subjects (P < .0001); RV LWLS increase (ΔRV LWLS) during exercise was lower in patients with IPF vs control patients (P < .00001). By multivariable analysis, RV LWLS at rest and ΔRV LWLS were directly related to peak exertion capacity, PAPs, and blood oxygen saturation level (Spo2; P < .0001). Δ RV LWLS was directly related to diffusion lung carbon monoxide (P < .0001).Conclusions: RV myocardial dysfunction is already present at rest in early-stage IPF and worsens during exertion as detected by two-dimensional speckle-tracking echocardiography. The RV altered contractile reserve appears to be related to reduced exercise tolerability and impaired pulmonary hemodynamic. [ABSTRACT FROM AUTHOR]

It has been demonstrated that interstitial fluid (IF) flow can play a crucial role in tumor cell progression. In the seminal works by Swartz and collaborators (Fleury et al., 2006; Shields et al., 2007) it was discovered that due to this flow, chemokine ligands secreted by tumor cells selectively tend to bind to receptors (CCR7) on the downstream side of the cells that in turn stimulate cells to migrate in the direction of the flow. This migration process was denoted as autologous chemotaxis. Previous mathematical modeling of autologous chemotaxis apparently has been restricted to single-phase considerations. The purpose of this work is to explore how a multiphase approach can be used where the fluid and cancer cells are treated as two separate phases with their own momentum balance equations. A mathematical model is derived that sheds light on essential nonlinear coupling mechanisms and interactions that are involved. The role played by fluid-ECM (friction type of term) and cell-ECM interaction forces (adhesion forces) are demonstrated. In particular, a fluid generated stress term in the mathematical expression for the cell velocity is highlighted. This term reflects how the flowing fluid will try to push the cancer cells in the downstream direction whose effect must be counterbalanced by the cancer cells by creating a sufficiently strong cell-ECM resistance force. Moreover, in order to represent the autologous chemotaxis migration mechanism we include (i) a component to represent stagnant ECM concentration (collagen); (ii) a chemical component representing chemokine that can convect with the fluid; and (iii) a third chemical component to represent protease secreted by the cancer cells which is able to release ECM-bound chemokine through proteolytic activity. The resulting model allows us to demonstrate how the autologous chemotaxis transport mechanism is governed by formation of chemokine concentration gradients that are asymmetric and skewed in the flow direction. We test the model behavior for a flow system with an external imposed pressure gradient which is comparable with the laboratory experiments by Swartz and collaborators. Sensitivity to changes in circumstances like blocking of the CCR7 receptor needed for autologous chemotaxis and elimination of the pressure driven IF flow (i.e., no flow) are explored and discussed. We also illustrate the model behavior in an envisioned tumor setting where increased IF flow is produced from leaky blood vessels that sit on the inside of the tumor. An increased fluid flow towards the region on the outside of the tumor is then generated where it is adsorbed by lymphatic vessels and gives rise to a characteristic elevated IF pressure profile that decreases at the tumor periphery. In turn, this results in an autologous chemotactic driven migration of cancer cells at the rim of the tumor. The simulation illustrates how the autologous chemotactic cell migration mechanism discovered by Swartz and collaborators possibly can be used as a means for metastasis by generating aggressive cell migration towards lymphatic vessels. [ABSTRACT FROM AUTHOR]

With the development of ultra‐high definition (UHD) display technology and stereoscopic 3D display technology, 3D ultra‐high monitor will help surgeons obtain the spatial hierarchy of internal tissues, identify tissue surfaces and blood vessels clearly, locate the focus precisely and reduce surgery time. Compared with normal 2D medical monitors, 3D medical monitors will lose more brightness because of the 3D application, so it is necessary to design a high‐brightness backlight system to guarantee the display stability and the accuracy of the diagnosis. This paper presents a novel processing system for 4K UHD 3D medical monitor with the architecture combined with universal SOC (system on a chip) and specialized FPGA (field programmable gate array). A hardware system is designed with high efficiency and reliable brightness stability control for small‐ and medium‐sized monitors. Furthermore, we analyze the two dimming modes of linear dimming and PWM dimming for a better application in medical monitor. This paper presents a novel processing system for 4K UHD 3D medical monitor with the architecture combined with universal SOC and specialized FPGA. A hardware system is with high efficiency and reliable brightness stability control for small‐ and medium‐sized monitors. Furthermore, we analyze the linear dimming and PWM dimming for a better application in medical monitor. [ABSTRACT FROM AUTHOR]

Although the resting ankle–brachial index (ABI) is commonly used as a tool to diagnose peripheral artery disease (PAD), several additional indices measured after exercise may have increased sensitivity for identifying PAD. The aim of this study was to determine the utility of resting ABI and three post-exercise physiological parameters for diagnosing PAD confirmed by arterial imaging studies. For each qualifying study, we assessed the performance measures for identifying PAD for resting ABI < 0.90, exercise ABI < 0.90, a decrease in ABI > 20% with exercise, and a decrease in ankle pressure > 30 mmHg with exercise. Of the 199 exams that met our inclusion criteria, imaging showed a > 75% stenotic lesion in at least one limb in 138 (69%) of patients. For stenoses > 75%, resting ABI < 0.90 had a sensitivity of 64% (95% CI: 56–72%) and exercise ABI < 0.90 had a sensitivity of 88% (95% CI: 82–93%). The sensitivity for a post-exercise ABI decrease > 20% was 67% (95% CI: 59–75%) and the sensitivity for a decrease in ankle pressure > 30 mmHg was 4% (95% CI: 2–9%). For individuals with a normal resting ABI but stenotic lesions > 75% confirmed by imaging (n=49), the addition of exercise ABI testing correctly identified an additional 25% of this population. Overall, exercise ABI < 0.90 exhibits a greater sensitivity for detecting PAD compared to resting ABI. Furthermore, exercise ABI < 0.90 had added clinical utility in patients with normal resting ABIs and was superior to other commonly used exercise indices. [ABSTRACT FROM AUTHOR]

Introduction: The main aim of the present study is to evaluate the effects of strenuous exercise, related to special military training for riot control, on systemic microvascular endothelial function and skin capillary density.Materials and Methods: Endothelium-dependent microvascular reactivity was evaluated in the forearm skin of healthy military trainees (age 23.4 ± 2.3 yr; n = 15) using laser speckle contrast imaging coupled with cutaneous acetylcholine (ACh) iontophoresis and post-occlusive reactive hyperemia (PORH). Functional capillary density was assessed using high-resolution, intra-vital color microscopy in the dorsum of the middle phalanx. Capillary recruitment (capillary reserve) was evaluated using PORH. Microcirculatory tests were performed before and after a 5-wk special military training for riot control.Results: Microvascular endothelium-dependent vasodilatory responses were markedly and significantly reduced after training, compared with values obtained before training. The peak values of microvascular conductance obtained during iontophoresis of ACh or PORH before training (0.84 ± 0.22 and 0.94 ± 0.72 APU/mmHg, respectively) were markedly reduced after training (0.47 ± 0.11 and 0.71 ± 0.14 APU/mmHg; p < 0.0001 and p = 0.0037, respectively). Endothelium-dependent capillary recruitment was significantly reduced after training (before 101 ± 9 and after 95 ± 8 capillaries/mm2; p = 0.0007).Conclusions: The present study showed that a 5-wk strenuous military training, performed in unfavorable climatic conditions, induces marked systemic microvascular dysfunction, mainly characterized by reduced endothelium-dependent microvascular vasodilation and blunted capillary recruitment. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effects on aortoiliac fluid dynamics after the implantation of an endograft based on endovascular aneurysm sealing (EVAS) versus endovascular aneurysm repair (EVAR) strategy. Methods: An adaptive geometrical deformable model was used for aortic lumen segmentation in 8 patients before and after the surgery. Abdominal aneurysms were treated with an endograft based on the EVAS system (Nellix, n = 4) and with a device based on an anatomical fixation technology (n = 4). Pressure, blood velocity, and wall shear stress (WSS) were estimated at different aortic regions using computational fluid dynamics methods. Physiologic inlet/outlet flow values at the abdominal aorta, the celiac trunk, and the mesenteric and the renal arteries were set. Pressure references were set at iliac arteries outlet. Results: Maximum aneurysm sizes were similar for both groups in the preoperative scans. The lumen area was lower after EVAR (P < .05) and EVAS (P < .01) compared to preoperative aortic lumen sizes. Pressure increase was higher in the proximal abdominal aorta after EVAS compared to EVAR (2.3 ± 0.3 mm Hg vs 0.9 ± 0.3 mm Hg, P < .001). Peak blood velocities inside the endografts were 3-fold higher for EVAS compared to EVAR (54 ± 5 cm/s vs 17 ± 4 cm/s, P < .01). Velocities at the iliac arteries also remained higher for EVAS (38 ± 4 cm/s vs 24 ± 4 cm/s, P < .05). Peak WSS at the iliac arteries remained higher for EVAS compared to EVAR group (P < .05). Conclusion: The significant modification of the aortic bifurcation anatomy after EVAS alters aortoiliac fluid dynamics, showing a pressure impact at the renal arteries level and an acceleration of the blood velocity at the iliac region with a concomitant increase in peak WSS. [ABSTRACT FROM AUTHOR]

Abstract Cytoglobin is a widely expressed heme protein that binds oxygen, carbon monoxide and nitric oxide. Recent examination of cytoglobin in the vasculature indicates that it contributes to nitric oxide availability, which is central to normal blood vessel function through regulation of smooth muscle cell tone and physiological response. Given the potential implications of cytoglobin in vascular function, we examined how cytoglobin might be uniquely regulated in vascular smooth muscle cells. Our data demonstrate that endothelial cells can increase the expression of cytoglobin in vascular smooth muscle cells, and the induction of cytoglobin is cell contact-dependent. We show that Notch signaling is necessary for endothelial cell-induced cytoglobin expression and Notch2 and Notch3 are sufficient to drive its expression in aortic smooth muscle cells. We further reveal that in cytoglobin -depleted smooth muscle cells there is increased cellular nitric oxide. These data demonstrate that, in addition to being the main producer of vascular nitric oxide, endothelial cells facilitate the ability of smooth muscle cells to metabolize nitric oxide through upregulation of cytoglobin. Our results reveal a novel mechanism by which Notch signaling contributes to vascular function through regulation of a gene that controls nitric oxide levels. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Replacing a portion of a glucose challenge with whole eggs (EGG) or egg whites (WHITE) was shown to protect against glucose-induced impairments in vascular function. We hypothesised in the present study that previously observed vasoprotection following co-ingestion of EGG or WHITE with glucose was attributed to limiting postprandial hyperglycaemia-induced oxidative stress that improves NO∙ bioavailability. Prediabetic men completed a randomised, cross-over study in which they ingested isoenergetic meals containing 100 g glucose (GLU), or 75 g glucose with 1·5 EGG, seven WHITE or two egg yolks (YOLK). At 30 min intervals for 3 h, we assessed plasma NO∙ metabolites, the lipid peroxidation biomarker malondialdehyde, antioxidants, arginine and its methylated metabolites (asymmetric dimethylarginine and symmetric dimethylarginine), tetrahydrobiopterin redox status, vasoconstrictors and inflammatory markers. Compared with GLU, malondialdehyde was lower and NO∙ metabolites were greater in EGG and WHITE, but YOLK was not different from GLU. Malondialdehyde was inversely correlated with NO∙ metabolites and vascular function, whereas NO∙ metabolites were positively correlated with vascular function. Compared with GLU, arginine was greater, but asymmetric and symmetric dimethylarginine and angiotensin-II were lower in all egg-based meals. Antioxidants, tetrahydrobiopterin redox status and inflammatory markers did not differ among treatments. Thus, while each egg-based meal improved arginine metabolism, only EGG and WHITE limited lipid peroxidation. This suggests that vasoprotection mediated by EGG and WHITE likely occurs in an NO∙-dependent manner by improving arginine metabolism and attenuating oxidative stress that otherwise limit NO∙ biosynthesis and bioavailability to the vascular endothelium. [ABSTRACT FROM AUTHOR]

Vascularisation is key to developing large transplantable tissue constructs capable of providing therapeutic benefits. The vascularised tissue engineering chamber originates from surgical concepts in tissue prefabrication and microsurgery. It serves as an in vivo bioreactor in the form of a closed, protected space surgically created and embedded within the body by fitting a noncollapsible chamber around major blood vessels. This creates a highly angiogenic environment which facilitates the engraftment and survival of transplanted cells and tissue constructs. This article outlines the chamber concept and explores its application in the context of recent advances in biomedical engineering, and how this can play a role in the future of cell therapies and regenerative medicine. Highlights The chamber acts as an in vivo bioreactor to facilitate the survival and development of cells and tissue constructs in a well-vascularised protected environment. Chamber tissues can be developed in an ectopic site away from diseased host tissue until maturity, and then the diseased host tissue can be replaced with this newly bioengineered tissue by secondary transplantation into the appropriate anatomical site. Large animal models (rabbits, pigs, sheep) and humans have had the chamber device tested, demonstrating the ability to upscale this technology and its clinical relevance. [ABSTRACT FROM AUTHOR]

Objective: To compare first trimester 2D conventional and 3D power Doppler angiography measures in twins and singletons following assisted reproduction. Methods: We prospectively evaluated 50 singleton and 47 twin pregnancies that eventually ended in live births. Patients were recruited from a single assisted reproductive technology (ART) center with standard treatment protocols. Obstetric ultrasound was performed at 8–9 weeks +6 days. Intervillous flow, uteroplacental circulation and uterine artery pulsatility (PI) and resistance index (RI) using two-dimensional (2D) ultrasound examination were evaluated. Using three-dimensional (3D) power Doppler angiography, placental volume and the 3D power Doppler indices from the intervillous and uteroplacental circulation were calculated. Results: Demographic and cycle characteristics were similar in mothers of singletons and twins. Placental volume was significantly (1.6-fold) larger in twins. Vascular density and blood perfusion in the intervillous space were lower in twins. The comparison of the other parameters did not show significant differences between singletons and twins. Conclusion: The data confirm the larger placental volume in twins, denoting a probable higher production of placental hormones that would support an early twin pregnancy. The lower vascular density and blood perfusion in the intervillous space in twins may also confer a reproductive advantage to them. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant growth of blood vessels in the choroid layer of the eye, termed choroidal neovascularization (CNV), is the pathological hallmark of exudative age-related macular degeneration (AMD), causing irreversible blindness among the elderly. Co-localization of proangiogenic factors and hypoxia inducible factors (HIF) in neovascular membranes from AMD eyes suggests the role of hypoxia in pathogenesis of CNV. In order to utilize hypoxic conditions in RPE for therapeutic purposes, we developed an optimized hypoxia regulated, RPE cell-specific gene therapy to inhibit choroidal neovascularization. An adeno-associated virus (AAV2) vector comprising a RPE-specific promoter and HIF-1 response elements (HRE) was designed to regulate production of human endostatin (a powerful angiostatic protein) in RPE. The vector was tested in a mouse model of laser-induced CNV using subretinal delivery. Spectral domain optical coherence tomography (SD-OCT) images from live mice and confocal images from lectin stained RPE flat mount sections demonstrated reduction in CNV areas by 80% compared to untreated eyes. Quantitative real-time polymerase chain reaction (qPCR) confirmed exogenous endostatin mRNA expression from the regulated vector that was significantly elevated 3, 7, and 14 days following laser treatment, but its expression was completely shut off after 45 days. Thus, RPE-specific, hypoxia-regulated delivery of anti-angiogenic proteins could be a valuable therapeutic approach to treat neovascular AMD at the time and in the ocular space where it arises.Key points: An optimized gene therapy vector targeting hypoxia and tissue-specific expression has been designed.The inhibitory role of gene therapy vector was tested in a mouse model of laser-induced CNV.An 80% reduction in choroidal neovascularization was achieved by the optimized vector.The expression of endostatin was limited to retinal pigment epithelium and regulated by hypoxia. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine whether differences in vascular responsiveness associated with training status would be more prominent in the trained limb (leg) than in the untrained limb (arm) microvasculature.Methods: Thirteen untrained (26 ± 5 year) and twelve trained (29 ± 4 year) healthy men were submitted to a vascular occlusion test (VOT) (2 min baseline, 5 min occlusion, and 8 min re-oxygenation). The oxygen saturation signal (StO2) was assessed using near-infrared spectroscopy (NIRS) throughout the VOT. Vascular responsiveness within the microvasculature was evaluated by the re-oxygenation Slope 2 (Slope 2 StO2) and the area under the curve (StO2AUC) of (StO2) signal during re-oxygenation in the leg and arm.Results: There was a significant interaction between training status and limb for the slope 2 StO2 (P < 0.01). The leg of the trained group showed a steeper slope 2 StO2 (1.35 ± 0.12% s-1) when compared to the slope 2 StO2 of the leg in their untrained counterparts (0.86 ± 0.09% s-1) (P < 0.05). There was a medium effect size of 0.58 for slope 2 StO2 on the arm and a large effect size of 1.21 for slope 2 StO2 on the leg. In addition, there was a small effect size of 0.24 for StO2AUC on the arm and a medium effect size of 0.64 for StO2AUC on the leg.Conclusion: The present study suggests that the vascular adaptations induced by lower limb endurance exercise training are more prominent in the trained limb than in the untrained limb microvasculature. [ABSTRACT FROM AUTHOR]

Canadian physical activity guidelines recommend older adults accumulate 150 min of weekly moderate to vigorous physical activity (MVPA). Older adults who are insufficiently active may have reduced blood vessel health and an increased risk of cardiovascular disease. We tested this hypothesis in 11 older adults who did (7 female; age, 65 ± 5 years; MVPA, = 239 ± 81 min/week) and 10 older adults who did not (7 female; age, 68 ± 9 years; MVPA, 95 ± 33 min/week) meet MVPA guidelines. Flow-mediated dilation (FMD) in the brachial (BA) and popliteal (POP) arteries, as well as nitroglycerin-mediated dilation (NMD; endothelial-independent dilation) in the POP were assessed via ultrasonography. Aerobic fitness (peak oxygen uptake) was determined using a graded, maximal cycle ergometry test via indirect calorimetry. MVPA and sedentary time were assessed over 5 days using the PiezoRx and activPAL, respectively. There were no differences in peak oxygen uptake (26 ± 10 vs. 22 ± 10 mL O2/(kg·min); p = 0.26) or sedentary time (512 ± 64 vs. 517 ± 76 min/day; p = 0.87) between groups; however, those who achieved the MVPA guidelines had a higher BA-FMD (5.1% ± 1.3% vs. 3.6% ± 1.7%; p = 0.03), POP-FMD (2.6% ± 1.1% vs. 1.3% ± 0.8%; p = 0.006), and POP-NMD (5.1% ± 1.7% vs. 3.3% ± 2.1%; p = 0.04). In the pooled sample, MVPA was moderately correlated to both BA-FMD (r = 0.53; p = 0.01) and POP-NMD (r = 0.59; p = 0.005), and strongly correlated to POP-FMD (r = 0.85; p < 0.001). Collectively, our results provide supporting evidence that meeting MVPA guidelines is associated with better vascular function and may reduce the risk of developing cardiovascular disease in older adults. Furthermore, these data suggest that weekly MVPA time may have a greater impact on blood vessel function than aerobic fitness and weekly sedentary time. [ABSTRACT FROM AUTHOR]

Background: During normal pregnancy, placental oxidative stress (OS) is present during all three trimesters and is necessary to obtain normal cell function. However, if OS reaches a certain level, pregnancy complications might arise. In preeclampsia (PE), a dangerous pregnancy specific hypertensive disorder, OS induced in the ischemic placenta causes a systemic inflammatory response and activates maternal endothelial cells. In this study, we aimed to quantify superoxide concentrations (as a measure of systemic OS) using electron paramagnetic resonance (EPR) and correlate them to markers of systemic inflammation, iron status and vascular function. Methods: Fifty-nine women with a healthy pregnancy (HP), 10 non-pregnant controls (NP) and 28 PE patients (32±3.3weeks) were included. During HP, blood samples for superoxide, neutrophil to lymphocyte ratio (NLR), mean platelet volume (MPV) and iron status were taken at 10, 25 and 39 weeks. Vascular measurements for arterial stiffness (carotid-femoral pulse wave velocity (CF-PWV), augmentation index (AIx), augmentation Pressure (AP)) and microvascular endothelial function (reactive hyperemia index (RHI)) were performed at 35 weeks. In PE, all measurements were performed at diagnosis. CMH (1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine) was used as spin probe for EPR, since the formed CM radical corresponds to the amount of superoxide. Results: Superoxide concentration remains stable during pregnancy (p = 0.92), but is significantly higher compared to the NP controls (p<0.0001). At 25 weeks, there is a significant positive correlation between superoxide and ferritin concentration. (p = 0.04) In PE, superoxide, systemic inflammation and iron status are much higher compared to HP (all p<0.001). During HP, superoxide concentrations correlate significantly with arterial stiffness (all p<0.04), while in PE superoxide is significantly correlated to microvascular endothelial function (p = 0.03). Conclusions: During HP there is an increased but stable oxidative environment, which is correlated to ferritin concentration. If superoxide levels increase, there is an augmentation in arterial stiffness. In PE pregnancies, systemic inflammation and superoxide concentrations are higher and result in a deterioration of endothelial function. Together, these findings support the hypothesis that vascular function is directly linked to the amount of OS and that measurement of OS in combination with vascular function tests might be used in the prediction of PE. [ABSTRACT FROM AUTHOR]

Summary: Background: The aim of this study was to determine the effects of obesity on myocardial mechanics and ventriculo‐arterial coupling (V‐A) in children. Methods: Strain parameters, stroke volume, arterial elastance, left ventricular (LV) elastance and V‐A were compared after adjusting for age and hypertension and after multivariate sub‐group analysis between patients with and without obesity. Results: Among 123 retrospectively enrolled subjects, 6–21 years age, 79.7% males, 52% were obese. Median (range) Body Mass Index Z score was +2.35 (1.67–4.43) for obese and +0.68 (−2.48–1.63) for non‐obese. Subjects with obesity had higher LV mass indexed2.7 (LVMI2.7) compared with non‐obese (P < 0.001). Lower global longitudinal strain (GLS) (P = 0.012), global circumferential strain (GCS) (P = 0.004), average longitudinal strain rate (P = 0.002) and average circumferential strain rate (P < 0.001) were seen in subjects with obesity; no difference was noted in arterial elastance, LV end systolic elastance and V‐A. Increased LVMI2.7, decreased GLS, GCS, average longitudinal strain rate, average circumferential strain rate and maintained V‐A were noted in the multivariate analysis between subgroups. Conclusions: Obesity causes alterations in myocardial mechanics with preserved V‐A in children. These findings may aid intervention in preventing the long‐term cadiovascular effects of obesity. [ABSTRACT FROM AUTHOR]

Background: Coarctation of the aorta (CoA) can be treated using surgery, balloon angioplasty, or stent implantation. Although short-term results are excellent with all three treatment modalities, long-term cardiovascular (CV) morbidity and mortality remain high, likely due to persistently abnormal vascular function. The effects of treatment modality on long-term vascular function remain uncharacterized. The goal of this study is to assess vascular function in this patient population for comparison among the treatment modalities. Methods: We will prospectively assess vascular Afunction in large and small arteries fusing multiple noninvasive modalities and compare the results among the three groups of CoA patients previously treated using surgery, balloon angioplasty, or stent implantation after frequency matching for confounding variables. A comprehensive vascular function assessment protocol has been created to be used in 7 centers. Our primary outcome is arterial stiffness measured by arterial tonometry. Inclusion and exclusion criteria have been carefully established after consideration of several potential confounders. Sample size has been calculated for the primary outcome variable. Conclusion: Treatment modalities for CoA may have distinct impact on large and small arterial vascular function. The results of this study will help identify the treatment modality that is associated with the most optimal level of vascular function, which, in the long term, may reduce CV risk. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether metrics of brain tissue integrity derived from postmortem magnetic resonance imaging (MRI) are associated with late-life cognitive decline, independent of cerebral vessel disease. Using data from 554 older adults, we used voxelwise regression to identify regions where the postmortem MRI transverse relaxation rate constant R 2 was associated with the rate of decline in global cognition. We then used linear mixed models to investigate the association between a composite R 2 measure and cognitive decline, controlling for neuropathology including 3 indices of vessel disease: atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. This composite R 2 measure was associated with the rate of decline (0.049 unit annually per R 2 unit, p < 0.0001) and accounted for 6.1% of its variance, beyond contributions from vessel disease indices and other prominent age-related neuropathologies. Thus, postmortem brain R 2 reflects disease processes underlying cognitive decline that are not captured by vessel disease indices or other standard neuropathologic indices and may provide a measure of brain tissue integrity that is complementary to histopathologic evaluation. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the "mountains" of obstacles in this field and elucidate these fundamental tenets of pulmonary vascular metabolism, such work has the potential to usher in much-needed diagnostic and therapeutic approaches for the mitochondrial and metabolic management of PH. [ABSTRACT FROM AUTHOR]

Introduction: Preeclampsia is a major health problem in human pregnancy, severely complicating 5–8% of all pregnancies. The emerging molecular mechanism is that conditions like hypoxic stress trigger the release of placental messengers into the maternal circulation, which causes preeclampsia. Our objective was to develop an in vitro model, which can be used to further elucidate the molecular mechanisms of preeclampsia and which might be used to find a remedy. Methods: Human non-complicated term placentas were collected. Placental explants were subjected to severe hypoxia and the conditioned media were added to chorionic arteries that were mounted into a myograph. Contractile responses of the conditioned media were determined, as well as effects on thromboxane-A2 (U46619) induced contractility. To identify the vasoactive compounds present in the conditioned media, specific receptor antagonists were evaluated. Results: Factors released by placental explants generated under severe hypoxia induced an increased vasoconstriction and vascular contractility to thromboxane-A2. It was found that agonists for the angiotensin-I and endothelin-1 receptor released by placental tissue under severe hypoxia provoke vasoconstriction. The dietary antioxidant quercetin could partially prevent the acute and sustained vascular effects in a concentration-dependent manner. Discussion: Both the acute vasoconstriction, as well as the increased contractility to U46619 are in line with the clinical vascular complications observed in preeclampsia. Data obtained with quercetin supports that our model opens avenues for e.g. nutritional interventions aimed at treating or preventing preeclampsia. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The effect of NO on smooth muscle cell contractility is crucial in regulating vascular tone, blood flow, and O2 delivery. Quantitative predictions for interactions between the NO production rate and the myogenic response for microcirculatory blood vessels are lacking. Methods: We developed a computational model of a branching microcirculatory network with four representative classes of resistance vessels to predict the effect of endothelium‐derived NO on the microvascular pressure‐flow response. Our model links vessel scale biotransport simulations of NO and O2 delivery to a mechanistic model of autoregulation and myogenic tone in a simplified microcirculatory network. Results: The model predicts that smooth muscle cell NO bioavailability significantly contributes to resting vascular tone of resistance vessels. Deficiencies in NO seen during hypoxia or ischemia lead to a decreased vessel diameter for all classes at a given intravascular pressure. At the network level, NO deficiencies lead to an increase in pressure drop across the vessels studied, a downward shift in the pressure‐flow curve, and a decrease in the effective range of the autoregulatory response. Conclusions: Our model predicts the steady state and transient behavior of resistance vessels to perturbations in blood pressure, including effects of NO bioavailability on vascular regulation. [ABSTRACT FROM AUTHOR]

OBJECTIVES There is growing interest in the use of bilateral internal thoracic arteries (BITAs) for myocardial revascularization. This study sought to compare the balance between early benefits and long-term outcomes of skeletonized or non-skeletonized conduits and to determine whether differences in outcomes are affected by other patient risk factors. METHODS BITAs were used in 1504 cases with either SK or NSK conduits. Propensity matching was completed using 22 covariates identifying 441 pairs of patients. The primary outcomes are the sternal wound infection in the short term and the composite outcome of all-cause mortality, myocardial infarction, revascularization and congestive heart failure. Outcomes were assessed using paired analysis techniques and Cox proportional hazards regression models stratified using the matched pairs. RESULTS Incidences of in-hospital mortality and perioperative myocardial infarction were similar in both groups. There were fewer sternal wound infections in the SK group (5.4 vs 9.1%, P  = 0.033). Homogeneity testing of the relative risk estimates confirmed that there was a protective effect of skeletonization in men that was not demonstrated in women (P  = 0.020). SK had a protective effect in diabetics not seen in non-diabetics (P  = 0.048). The composite outcome of all-cause mortality, myocardial infarction, revascularization and congestive heart failure at a median of 5.6 years was comparable in both groups (hazard ratio 0.81, 95% confidence interval 0.57–1.15). CONCLUSION Skeletonization results in better perioperative outcomes and comparable cardiac outcomes in patients undergoing BITA with the greatest benefit in men and patients with chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

It is well established that laser phototherapy (LP) is contraindicated directly over cancer cells, due to its bio modulatory effects in cell and blood vessel proliferation. The aim of the present study was to analyze the influence of typical low-level laser therapy (LLLT) and high intensity laser therapy (HILT) and an in-between dose of 9 J on collagen fibers and blood vessels content in melanoma tumors (B16F10) implanted in mice. Melanoma tumor cells were injected in male Balb C mice which were distributed in four groups: control (no irradiated) or irradiated by 3, 9, or 21 J (150; 450, or 1050 J/cm2). LP was performed in daily sessions for 3 days with a InGaAlP-660 nm (mean output: 50 mW, spot size: 2 mm2). Tumor volume was analyzed using (1) picrosirius staining to quantify collagen fibers content and (2) Verhoeff's method to quantify blood vessels content. Tumor growth outcome measured in the 3-J group was not significantly different from controls. Nine and 21-J groups, presented significant and dose-dependent increases in tumor volume. Quantitative analysis of the intensity of collagen fibers and their organization in stroma and peri-tumoral microenvironment showed significant differences between irradiated and control group. Blood vessels count of 21-J group outnumbered the other groups. High doses (≥ 9 J) of LP showed a dose-dependent tumor growth, different collagen fibers characteristics, and eventually blood vessel growth, while a typical LLLT dose (3 J) appeared harmless on melanoma cell activity. [ABSTRACT FROM AUTHOR]

Resistance training promotes microvasculature expansion; however, it remains unknown how different resistance training programs contribute to angiogenesis. Thus, we recruited experienced resistance-trained participants and determined the effect of 12 wk of either high-repetition/low-load or low-repetition/high-load resistance training performed to volitional fatigue on muscle microvasculature. Twenty men performed either a high-repetition [20-25 repetitions, 30-50% of 1-repetition maximum (1RM); n = 10] or a low-repetition (8-12 repetitions, 75-90% of 1RM; n = 10) resistance training program. Muscle biopsies were taken before and after resistance training, and immunohistochemistry was used to assess fiber type (I and II)-specific microvascular variables. High-repetition/low-load and low-repetition/high-load groups were not different in any variable before resistance training. Both protocols resulted in an increase in capillarization. Specifically, after resistance training, the capillary-to-fiber ratio, capillary contacts, and capillary-to-fiber perimeter exchange index were elevated, and sharing factor was reduced. These data demonstrate that resistance training performed to volitional failure, using either high repetition/low load or low repetition/high load, induced similar microvascular adaptations in recreationally resistance-trained young men. [ABSTRACT FROM AUTHOR]

Human cell-based 3D tissue constructs play an increasing role in disease modeling and drug screening. Inflammation, atherosclerosis, and many autoimmune disorders involve the interactions between immune cells and blood vessels. However, it has been difficult to image and model these interactions under realistic conditions. In this study, we fabricated a perfusion and imaging chamber to allow the real-time visualization of leukocyte perfusion, adhesion, and migration inside a tissue-engineered blood vessel (TEBV). We monitored the elevated monocyte adhesion to the TEBV wall and transendothelial migration (TEM) as the TEBV endothelium was activated by the inflammatory cytokine TNF-α. We demonstrated that treatment with anti-TNF-α or an NF-kB signaling pathway inhibitor would attenuate the endothelium activation and reduce the number of leukocyte adhesion (＞74%) and TEM events (＞87%) close to the control. As the first demonstration of real-time imaging of dynamic cellular events within a TEBV, this work paves the way for drug screening and disease modeling in TEBV-associated microphysiological systems. [ABSTRACT FROM AUTHOR]

Abstract: Nerves and blood vessels are found in the peripheral annulus and endplates of healthy adult intervertebral discs. Degenerative changes can allow these vessels to grow inwards and become associated with discogenic pain, but it is not yet clear how far, and why, they grow in. Previously we have shown that physical disruption of the disc matrix, which is a defining feature of disc degeneration, creates free surfaces which lose proteoglycans and water, and so become physically and chemically conducive to cell migration. We now hypothesise that blood vessels and nerves in degenerated discs are confined to such disrupted tissue. Whole lumbar discs were obtained from 40 patients (aged 37–75 years) undergoing surgery for disc herniation, disc degeneration with spondylolisthesis or adolescent scoliosis (‘non‐degenerated’ controls). Thin (5‐μm) sections were stained with H&E and toluidine blue for semi‐quantitative assessment of blood vessels, fissures and proteoglycan loss. Ten thick (30‐μm) frozen sections from each disc were immunostained for CD31 (an endothelial cell marker), PGP 9.5 and Substance P (general and nociceptive nerve markers, respectively) and examined by confocal microscopy. Volocity image analysis software was used to calculate the cross‐sectional area of each labelled structure, and its distance from the nearest free surface (disc periphery or internal fissure). Results showed that nerves and blood vessels were confined to proteoglycan‐depleted regions of disrupted annulus. The maximum distance of any blood vessel or nerve from the nearest free surface was 888 and 247 μm, respectively. Blood vessels were greater in number, grew deeper, and occupied more area than nerves. The density of labelled blood vessels and nerves increased significantly with Pfirrmann grade of disc degeneration and with local proteoglycan loss. Analysing multiple thick sections with fluorescent markers on a confocal microscope allows reliable detection of thin filamentous structures, even within a dense matrix. We conclude that, in degenerated and herniated discs, blood vessels and nerves are confined to proteoglycan‐depleted regions of disrupted tissue, especially within annulus fissures. [ABSTRACT FROM AUTHOR]

A method for detection of the optic disc boundaries in fundus images is suggested. The method is based on integration of luminance samples along the diagonals. A modification of the method based on an algorithm of luminance sample integration in a fan pattern is also suggested. To reduce the effect of blood vessels on the results of integration, images are processed in the red channel. The method suggested in this work can be used for automating the description of fundus images in ophthalmology. [ABSTRACT FROM AUTHOR]

Aging is characterized by functional decline in homeostatic regulation and vital cellular events. This process can be linked with the development of cardiovascular diseases (CVDs). In this review, we discussed aging-induced biological alterations that are associated with CVDs through the following aspects: (i) structural, biochemical, and functional modifications; (ii) autonomic nervous system (ANS) dysregulation; (iii) epigenetic alterations; and (iv) atherosclerosis and stroke development. Aging-mediated structural and biochemical modifications coupled with gradual loss of ANS regulation, vascular stiffening, and deposition of collagen and calcium often disrupt cardiovascular system homeostasis. The structural and biochemical adjustments have been consistently implicated in the progressive increase in mechanical burden and functional breakdown of the heart and vessels. In addition, cardiomyocyte loss in this process often reduces adaptive capacity and cardiovascular function. The accumulation of epigenetic changes also plays important roles in the development of CVDs. In summary, the understanding of the aging-mediated changes remains promising towards effective diagnosis, discovery of new drug targets, and development of new therapies for the treatment of CVDs. [ABSTRACT FROM AUTHOR]

Objective: To examine the expression of hypoxia-inducible factor-1α (HIF-1α) and its related molecules (cellular repressor of E1A-stimulated genes [CREG], osteopontin [OPN], proto-oncogene tyrosine-protein kinase Src [c-Src], and vascular endothelial growth factor [VEGF]) in juvenile nasopharyngeal angiofibroma (JNA) and explore the correlation between clinical prognosis and HIF-1α expression. Methods: The study performed a retrospective review of the clinical records of patients with JNA treated between 2003 and 2007. Specimens were analyzed by immunohistochemistry for HIF-1α, CREG, OPN, c-Src, and VEGF expression, and microvessel density (MVD) was assessed by tissue microarray. The correlation between expression levels and clinicopathological features including age, tumor stage, intraoperative blood loss, and recurrence was analyzed. Results: HIF-1α, CREG, OPN, c-Src, and VEGF were upregulated in endothelial cells (ECs) of patients with JNA, and strong correlations in the expression of these molecules were observed. HIF-1α expression was higher in young patients (P = .032) and in recurrent cases (P = .01). Survival analysis showed that low HIF-1α levels in ECs predicted longer time to recurrence (log rank test P = .006). Receiver operating characteristic curve analysis showed that HIF-1α was a prognostic factor for recurrence (area under the curve = 0.690, P = .019). No correlation was found between the expression of molecules and Radkowski stage or intraoperative blood loss. Conclusion: In cases of JNA treated surgically, HIF-1α expression in ECs is a useful prognostic factor for tumor recurrence. [ABSTRACT FROM AUTHOR]

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue tumor that arises primarily on the trunk and extremities but seldom on the scalp. Several variants of DFSP have been described, including myxoid DFSP. Although typical DFSP may have focally myxoid areas, myxoid DFSP, in which most of the stroma is myxoid, is rare and can pose diagnostic challenges. Here, we report a case of myxoid DFSP with an unusual clinical presentation that could have been mistaken for a lipoma. Additionally, the myxoid DFSP displayed prominent vasculature in a myxoid stroma, which could have been mistaken for a myxoid liposarcoma. [ABSTRACT FROM AUTHOR]

Many cardiovascular diseases present renin-angiotensin-aldosterone system (RAAS) hyperactivity as an important pathophysiological mechanism to be target in the therapeutic approaches. Moreover, arterial stiffness is currently considered as a new independent risk factor for cardiovascular disease in different clinical conditions, including hypertension and chronic kidney disease. In fact, excessive stimulation of angiotensin type 1 (AT1) receptors, as well as mineralocorticoid receptors, results in cellular growth, oxidative stress and vascular inflammation, which may lead to arterial stiffness and accelerate the process of vascular aging. In the last decades, a vasoprotective axis of the RAAS has been discovered, and now it is well established that new components with antioxidant and anti-inflammatory properties play important roles promoting vasodilation, natriuresis and reducing collagen deposition, thus attenuating arterial stiffness and improving endothelial function. In this review, we will focus on these pathophysiological mechanisms and the relevance of RAAS inhibition by different strategies to increase arterial compliance and to decelerate vascular aging. [ABSTRACT FROM AUTHOR]

Alcohol abuse during pregnancy is a well-known factor in fetal morbidity, including smaller fetal size. We have shown that chronic hypoxia, considered the main pathogenetic factor in intrauterine growth restriction, elevates fetoplacental vascular resistance (and vasoconstrictor reactivity) and thus, presumably, reduces placental blood flow. We thus hypothesized that alcohol may affect the fetus - in addition to other mechanisms - by altering fetoplacental vascular resistance and/or reactivity. Using isolated, double-perfused rat placenta model, we found that maternal alcohol intake in the last third of gestation doubled the vasoconstrictor responses to angiotensin II but did not affect resting vascular resistance. Reactivity to acute hypoxic challenges was unchanged. Chronic maternal alcohol intake in a rat model alters fetoplacental vasculature reactivity; nevertheless, these changes do not appear as serious as other detrimental effects of alcohol on the fetus. [ABSTRACT FROM AUTHOR]

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Consumption of different PUFAs (polyunsaturated fatty acids) can induce functional changes in blood vessels via endothelial cells, which interact with dietary factors in the circulation. The basement membrane that separates the endothelium from the smooth muscle cells of the medial layer can also influence the functional state of endothelial cells. However, the effect of basement membrane on the endothelial response to dietary PUFAs in relation to growth state (e.g. proliferation versus quiescence) has never been investigated. We therefore compared the viability (CCK kit) and proliferation (bromodeoxyuridine incorporation) of EA.hy926 endothelial cells grown on Matrigel or collagen versus non-coated plates. EA.hy926 viability and proliferation were also assessed after treatment with 0–150 μM of PUFAs [linoleic acid (LA), arachidonic acid (AA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. Our study showed that only cells grown on Matrigel-coated plates reached quiescence after becoming confluent with a decreased level of MCM2 and p-cyclin D1 (T286), increased levels of p27kip1 and a low level of apoptosis and senescence. AA, EPA and DHA decreased the viability and proliferation of subconfluent cells grown on plastic dishes in a dose-dependent manner, while the presence of Matrigel made the cells resistant to these adverse effects. Confluent cell viability was less sensitive to higher concentrations of AA, EPA and DHA than subconfluent cells, and a significant increase in caspase-3 cleavage was only observed in confluent cells treated with DHA. Higher concentrations of AA, EPA and DHA suppressed DNA synthesis by both subconfluent and confluent cells, while precursor C18 PUFAs (LA and ALA) had no negative effects on viability and proliferation. Our study is the first to show that extracellular matrix and growth state are important factors in the EA.hy926 cell response to PUFAs, and that the mechanisms by which individual PUFAs operate may be growth state-dependent. [ABSTRACT FROM AUTHOR]

Background: Vitamin D (VitD) deficiency is prevalent in adolescents with type 1 diabetes (T1D) and is associated with diabetes‐related vascular complications in adulthood. The objective of this clinical trial was to assess VitD treatment on endothelial function (EF) and markers of renal inflammation, in this patient group. Methods: Adolescents with T1D with suboptimal levels of VitD (<37.5 nmol/L) were treated for 12 to 24 weeks with a VitD analog (VitD3) at doses of 1000 or 2000 IU daily. The primary end‐point assessed the change in reactive hyperemia index (lnRHI), a measure of EF. Secondary end‐points included changes in blood pressure, lipid profile, HbA1c and albumin creatinine ratio (ACR). Urinary cytokine/chemokine inflammatory profile was also assessed in a subset of subjects posttreatment. Results: Two hundred and seventy‐one subjects were screened for VitD status and 31 VitD deficient subjects with a mean age of 15.7 ± 1.4 years were enrolled and completed the study. Mean 25‐OH‐VitD levels significantly increased (33.0 ± 12.8 vs 67.0 ± 23.2 nmol/L, P < .01) with a significant improvement in EF following VitD supplementation (lnRHI 0.58 ± 0.20 vs 0.68 ± 0.21, P = .03). VitD supplementation did not significantly impact systolic blood pressure/diastolic blood pressure (SBP/DBP), lipids, HbA1c and ACR and no adverse effects were seen. Several urinary inflammatory cytokines/chemokines: MCP‐3 (P < .01), epidermal growth factor (EGF) (P < .01) tumor necrosis factor β (TNFβ) (P = .01), interleukin‐10 (IL‐10) (P = .01), also significantly decreased post‐VitD‐treatment. Conclusions: Treatment with VitD was associated with an improvement in EF and reduced expression of urinary inflammatory markers in adolescents with T1D. This data is suggestive of an additional benefit of VitD supplementation on early markers of microvascular complications. [ABSTRACT FROM AUTHOR]