Etto Eringa - Academia.edu (original) (raw)

Papers by Etto Eringa

Angiogenesis

Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and ... more Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myos...

Arteriosclerosis, Thrombosis, and Vascular Biology

Objective: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an earl... more Objective: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after t...

European Journal of Vascular and Endovascular Surgery

Frontiers in Physiology

Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in... more Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT. Methods: We studied PVAT and muscle resistance arteries (RA) from littermate IRS2 +/+ and IRS2 −/− mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2 +/+ RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2 +/+ and IRS2 −/− littermates to evaluate vasodilator properties of PVAT. Results: IRS2 −/− RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2 +/+ RA. IRS2 +/+ vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2 −/− RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2 +/+ PVAT (17 ± 4.8, p = 0.014), yet induced a 10 ± 7.6% decrease in diameter in the presence of IRS2 −/− PVAT. Adipocytes in IRS2 −/− PVAT (1314 ± 161 µm 2) were larger (p = 0.0013) than of IRS2 +/+ PVAT (915 ± 63 µm 2). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2 +/+ and IRS2 −/− PVAT, as were expression of pro-inflammatory genes (TNF-α, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2 −/− and IRS2 +/+ PVAT. Conclusion: In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion.

Clinical and Experimental Pharmacology and Physiology

American Journal of Physiology-Heart and Circulatory Physiology

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipos... more Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2−/− bone marrow to WT mice. Deletion of JNK2 in bone marrow re...

Physiological Reviews

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose... more Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.

Critical Care

Background: Arterial hyperoxia may induce vasoconstriction and reduce cardiac output, which is pa... more Background: Arterial hyperoxia may induce vasoconstriction and reduce cardiac output, which is particularly undesirable in patients who already have compromised perfusion of vital organs. Due to the inaccessibility of vital organs in humans, vasoconstrictive effects of hyperoxia have primarily been studied in animal models. However, the results of these studies vary substantially. Here, we investigate the variation in magnitude of the hyperoxia effect among studies and explore possible sources of heterogeneity, such as vascular region and animal species. Method: Pubmed and Embase were searched for eligible studies up to November 2017. In vivo and ex vivo animal studies reporting on vascular tone changes induced by local or systemic normobaric hyperoxia were included. Experiments with co-interventions (e.g. disease or endothelium removal) or studies focusing on lung, brain or fetal vasculature or the ductus arteriosus were not included. We extracted data pertaining to species, vascular region, blood vessel characteristics and method of hyperoxia induction. Overall effect sizes were estimated with a standardized mean difference (SMD) random effects model. Results: We identified a total of 60 studies, which reported data on 67 in vivo and 18 ex vivo experiments. In the in vivo studies, hyperoxia caused vasoconstriction with an SMD of − 1.42 (95% CI − 1.65 to − 1.19). Ex vivo, the overall effect size was SMD − 0.56 (95% CI − 1.09 to − 0.03). Between-study heterogeneity (I 2) was high for in vivo (72%, 95% CI 62 to 85%) and ex vivo studies (86%, 95% CI 78 to 98%). In vivo, in comparison to the overall effect size, hyperoxic vasoconstriction was less pronounced in the intestines and skin (P = 0.03) but enhanced in the cremaster muscle region (P < 0.001). Increased constriction was seen in vessels 15-25 μm in diameter. Hyperoxic constriction appeared to be directly proportional to oxygen concentration. For ex vivo studies, heterogeneity could not be explained with subgroup analysis. Conclusion: The effect of hyperoxia on vascular tone is substantially higher in vivo than ex vivo. The magnitude of the constriction is most pronounced in vessels~15-25 μm in diameter and is proportional to the level of hyperoxia. Relatively increased constriction was seen in muscle vasculature, while reduced constriction was seen in the skin and intestines.

Microcirculation (New York, N.Y. : 1994), 2018

To determine the human dose-response relationship between a stepwise increase in arterial oxygen ... more To determine the human dose-response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO and sublingual microcirculatory perfusion. Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF. Systemic DO was unchanged throughout the study (P = .8). PVD decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, P = .001). CI decreased linearly (max -10%, SD10, P < .001) due to a reduction in HR (max -10%, SD7, P = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa. In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO...

American journal of physiology. Heart and circulatory physiology, Jan 3, 2017

Myocardial contrast echocardiography (MCE) offers the opportunity to study myocardial perfusion d... more Myocardial contrast echocardiography (MCE) offers the opportunity to study myocardial perfusion defects in mice in detail. The value of MCE compared to SPECT, PET and CT consists of high spatial resolution, the possibility of quantification of blood volume and relatively low costs. Nevertheless, a number of technical and physiological aspects should be considered to ensure reproducibility among research groups. The aim of this overview is to describe technical aspects of MCE and the physiological parameters that influence myocardial perfusion data obtained with this technique. First, technical aspects of MCE discussed in this technical review are logarithmic compression of ultrasound data by ultrasound systems, saturation of the contrast signal and acquisition of images during different phases of the cardiac cycle. Second, physiological aspects of myocardial perfusion that are affected by the experimental design are discussed, including the anesthesia regimen, systemic cardiovascula...

Diabetes, Obesity and Metabolism

Preclinical studies have suggested that polyphenols extracted from red wine (RWPs) favourably aff... more Preclinical studies have suggested that polyphenols extracted from red wine (RWPs) favourably affect insulin sensitivity, but there is controversy over whether RWPs exert similar effects in humans. The aim of the present study was to determine whether RWPs improve insulin sensitivity in obese volunteers. Obese (body mass index >30 kg/m ) volunteers were randomly allocated to RWPs 600 mg/d (n = 14) or matched placebo (n = 15) in a double-blind parallel-arm study for 8 weeks. The participants were investigated at baseline and at the end of the study. Insulin sensitivity was determined using a hyperinsulinaemic-euglycaemic clamp (M-value), a mixed-meal test (Matsuda index), and homeostatic model assessment of insulin resistance (HOMA-IR). RWPs elicited no significant changes in M-value (RWP group: median [interquartile range; IQR] baseline 3.0 [2.4; 3.6]; end of study 3.3 [2.4; 4.8] vs placebo group: median [IQR] baseline 3.4 [2.8; 4.4]; end of study 2.9 [2.8; 5.9] mg/kg/min; P = .65), in Matsuda index (RWP group: median [IQR] baseline 3.3 [2.2; 4.8]; end of study 3.6 [2.4; 4.8] vs placebo group: median [IQR] baseline 4.0 [3.0; 6.0]; end of study 4.0 [3.0; 5.2]; P = .88), or in HOMA-IR. This study showed that 8 weeks of RWP supplementation did not improve insulin sensitivity in 29 obese volunteers. Our findings were not consistent with the hypothesis that RWPs ameliorate insulin resistance in human obesity.

Journal of the American Heart Association

Background Obesity is key feature of the metabolic syndrome and is associated with high cardiovas... more Background Obesity is key feature of the metabolic syndrome and is associated with high cardiovascular morbidity and mortality. Obesity is associated with macrovascular endothelial dysfunction, a determinant of outcome in patients with coronary artery disease. Here, we compared the influence of obesity on microvascular endothelial function to that of established cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, and smoking in patients with suspected coronary artery disease. Methods and Results Endothelial function was assessed during postocclusive reactive hyperemia of the brachial artery and downstream microvascular beds in 108 patients who were scheduled for coronary angiography. In all patients, microvascular vasodilation was assessed using peripheral arterial tonometry; laser Doppler flowmetry and digital thermal monitoring were performed. Body mass index was significantly associated with decreased endothelium‐dependent vasodilatation mea...

Journal of visualized experiments : JoVE, Jan 20, 2017

It has been demonstrated that insulin's vascular actions contribute to regulation of insulin ... more It has been demonstrated that insulin's vascular actions contribute to regulation of insulin sensitivity. Insulin's effects on muscle perfusion regulate postprandial delivery of nutrients and hormones to insulin-sensitive tissues. We here describe a technique for combining intravital microscopy (IVM) and contrast-enhanced ultrasonography (CEUS) of the adductor compartment of the mouse hindlimb to simultaneously visualize muscle resistance arteries and perfusion of the microcirculation in vivo. Simultaneously assessing insulin's effect at multiple levels of the vascular tree is important to study relationships between insulin's multiple vasoactive effects and muscle perfusion. Experiments in this study were performed in mice. First, the tail vein cannula is inserted for the infusion of anesthesia, vasoactive compounds and ultrasound contrast agent (lipid-encapsulated microbubbles). Second, a small incision is made in the groin area to expose the arterial tree of the a...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2017

In the past century, various techniques to measure adipose tissue perfusion in humans have been d... more In the past century, various techniques to measure adipose tissue perfusion in humans have been developed (Table). Most of these techniques are suitable for measuring subcutaneous adipose tissue perfusion, whereas visceral adipose tissue perfusion can only be measured by means of positron emission

Diabetes care, Apr 15, 2017

This study investigated whether the relationship between neuropathy and microvascular dysfunction... more This study investigated whether the relationship between neuropathy and microvascular dysfunction in patients with type 2 diabetes is independent of diabetes-related factors. For this purpose, we compared skin microvascular function in patients with type 2 diabetes with that of patients with cryptogenic axonal polyneuropathy (CAP), a polyneuropathy of unknown etiology. Cross-sectional information was collected from 16 healthy controls (HCs), 16 patients with CAP, 15 patients with type 2 diabetes with polyneuropathy (DPN), and 11 patients with type 2 diabetes without polyneuropathy. Axonal degeneration was assessed with skin biopsy and nerve conduction studies. Microvascular skin vasodilation was measured using laser Doppler fluxmetry combined with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Patients with CAP and DPN demonstrated a similar decrease in intraepidermal nerve fiber density and sural sensory nerve action potential compared with HCs. The vasodilato...

Proceedings of the Physiological Society, 2013

Arteriosclerosis Thrombosis and Vascular Biology, Mar 1, 2010

Several stress conditions are characterized by activation of 5#-AMP-activated protein kinase (AMP... more Several stress conditions are characterized by activation of 5#-AMP-activated protein kinase (AMPK) and the development of leucine resistance in skeletal muscle. In the present study, we determined whether direct activation of the AMPK by 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleoside (AICAR) prevents the characteristic leucine-induced increase in protein synthesis by altering mammalian target of rapamycin (mTOR) signal transduction. Rats were injected with AICAR or saline (Sal) and 1 h thereafter received an oral gavage of leucine (or Sal). Efficacy of AICAR was verified by increased AMPK phosphorylation. AICAR decreased basal in vivo muscle (gastrocnemius) protein synthesis and completely prevented the leucine-induced increase, independent of a change in muscle adenine nucleotide concentration. AICAR also prevented the hyperphosphorylation of eukaryotic initiation factor (eIF) 4E binding protein (4E-BP1), ribosomal protein S6 kinase (S6K1), S6, and eIF4G in response to leucine, suggesting a decrease in mTOR activity. Moreover, AICAR prevented the leucineinduced redistribution of eIF4E from the inactive eIF4EÁ4E-BP1 to the active eIF4EÁeIF4G complex. This ability of AICAR to produce muscle leucine resistance could not be attributed to a change in phosphorylation of tuberous sclerosis complex (TSC)2, the formation of a TSC1ÁTSC2 complex, the binding of raptor with mTOR, or the phosphorylation of eukaryotic elongation factor-2. However, the inhibitory actions of AICAR were associated with reduced phosphorylation of proline-rich Akt substrate-40 and increased phosphorylation of raptor, which represent potential mechanisms by which AICAR might be expected to inhibit leucine-induced increases in mTOR activity and protein synthesis under in vivo conditions.