Small bowel lesions in patients with iron deficiency anaemia without overt bleeding: a multicentre study.

The diagnostic work-up in iron deficiency anaemia (IDA) patients can be challenging when bleedings or malabsorption are not clinically manifest. Lesions on the small bowel mucosa may cause IDA. We evaluated the prevalence of lesions on the small bowel mucosa detected at Videocapsule Endoscopy (VCE) in IDA patients following negative upper and lower endoscopies.

Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells.

The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. To date, the role of APP in vasculature and endothelial cells has not been fully elucidated.

Publisher Correction: N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA-dependent neovascularization.

The original version of this Article contained errors in Figures 1, 3 and 4. In panels b and d of Figure 1, the labels 'Sdc4' were inadvertently replaced by 'Sdc4'. In panels c and d of Figure 3, the labels 'Sdc4' were replaced by 'Sdc2'.

N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA-dependent neovascularization.

The proteoglycan Syndecan-2 (Sdc2) has been implicated in regulation of cytoskeleton organization, integrin signaling and developmental angiogenesis in zebrafish. Here we report that mice with global and inducible endothelial-specific deletion of Sdc2 display marked angiogenic and arteriogenic defects and impaired VEGFA signaling. No such abnormalities are observed in mice with deletion of the closely related Syndecan-4 (Sdc4) gene.

Bradykinin B2 Receptor Contributes to Inflammatory Responses in Human Endothelial Cells by the Transactivation of the Fibroblast Growth Factor Receptor FGFR-1.

Elevated levels of bradykinin (BK) and fibroblast growth factor-2 (FGF-2) have been implicated in the pathogenesis of inflammatory and angiogenic disorders. In angiogenesis, both stimuli induce a pro-inflammatory signature in endothelial cells, activating an autocrine/paracrine amplification loop that sustains the neovascularization process. Here we investigated the contribution of the FGF-2 pathway in the BK-mediated human endothelial cell permeability and migration, and the role of the B2 receptor (B2R) of BK in this cross-talk.

Peptides derived from the histidine-proline rich glycoprotein bind copper ions and exhibit anti-angiogenic properties.

The role of copper in cancer progression has been established since decades. Additionally, copper is able to stimulate angiogenesis through the control of VEGF expression and activity in endothelial cells. In this paper a tetrapeptide, belonging to the histidine-proline-rich glycoprotein (HPRG) and encompassing four repeats of the sequence GHHPH (named TetraHPRG), was synthesized and its copper(ii) complex species were characterized by means of potentiometry, UV-vis, circular dichroism (CD), electron paramagnetic resonance (EPR) and electron spray ionization mass spectrometry (ESI-MS).

The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling.

As a master regulator of endothelial cell function, vascular endothelial growth factor receptor-2 (VEGFR2) activates multiple downstream signaling pathways that are critical for vascular development and normal vessel function. VEGFR2 trafficking through various endosomal compartments modulates its signaling output. Accordingly, proteins that regulate the speed and direction by which VEGFR2 traffics through endosomes have been demonstrated to be particularly important for arteriogenesis.

Modulation of VEGF receptor 2 signaling by protein phosphatases.

Phosphorylation of serines, threonines, and tyrosines is a central event in signal transduction cascades in eukaryotic cells. The phosphorylation state of any particular protein reflects a balance of activity between kinases and phosphatases. Kinase biology has been exhaustively studied and is reasonably well understood, however, much less is known about phosphatases.

Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development.

The role of fluid shear stress in vasculature development and remodeling is well appreciated. However, the mechanisms regulating these effects remain elusive. We show that abnormal flow sensing in lymphatic endothelial cells (LECs) caused by Sdc4 or Pecam1 deletion in mice results in impaired lymphatic vessel remodeling, including abnormal valve morphogenesis.

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling.

The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery.

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling.

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4(-/-)) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4(-/-) mice were poorly aligned in the direction of the flow.

E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role.

Ischemia/reperfusion (I/R) elicits renin release from cardiac mast cells (MC), thus activating a local renin-angiotensin system (RAS), culminating in ventricular fibrillation. We hypothesized that in I/R, neurogenic ATP could degranulate juxtaposed MC and that ecto-nucleoside triphosphate diphosphohydrolase 1/CD39 (CD39) on MC membrane could modulate ATP-induced renin release. We report that pharmacological inhibition of CD39 in a cultured human mastocytoma cell line (HMC-1) and murine bone marrow-derived MC with ARL67156 (100 µM) increased ATP-induced renin release (≥2-fold), whereas purinergic P2X7 receptors (P2X7R) blockade with A740003 (3 µM) prevented it.

The syndecan-4/protein kinase Cα pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo.

Prostaglandin E2 (PGE2) is regarded as the main mediator of inflammatory symptoms. In addition, it also plays an important role in tumor growth and angiogenesis. In this study, we examined the mechanism of PGE2-induced angiogenic response.

Mitochondrial aldehyde dehydrogenase-2 activation prevents β-amyloid-induced endothelial cell dysfunction and restores angiogenesis.

Amyloid β peptides (Aβ1-40 and Aβ1-42) cause cerebral degeneration by impairing the activity of angiogenic factors and inducing apoptosis and senescence in the endothelium. Amyloid peptides are known to induce oxidative stress. Impairment of mitochondrial aldehyde dehydrogenase 2 (ALDH2) following oxidative stress, results in accumulation of toxic aldehydes, particularly 4-hydroxynoneal (4-HNE).

The expression level of ecto-NTP diphosphohydrolase1/CD39 modulates exocytotic and ischemic release of neurotransmitters in a cellular model of sympathetic neurons.

Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves, whereas transmitter ATP is catabolized by ecto-NTP diphosphohydrolase 1 (E-NTPDase1)/CD39, an ecto-ATPase. Because ATP is known to modulate neurotransmitter release at prejunctional sites, we questioned whether this action may be ultimately controlled by the expression of E-NTPDase1/CD39 at sympathetic nerve terminals. Accordingly, we silenced E-NTPDase1/CD39 expression in nerve growth factor-differentiated PC12 cells, a cellular model of sympathetic neuron, in which dopamine is the predominant catecholamine.

Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells.

Background: Renin released by ischemia/reperfusion from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (ventricular tachycardia and fibrillation), making RAS a new therapeutic target in myocardial ischemia.

Methods And Results: We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea pig hearts ex vivo.

Interaction between sensory C-fibers and cardiac mast cells in ischemia/reperfusion: activation of a local renin-angiotensin system culminating in severe arrhythmic dysfunction.

Renin, the rate-limiting enzyme in the activation of the renin-angiotensin system (RAS), is synthesized and stored in cardiac mast cells. In ischemia/reperfusion, cardiac sensory nerves release neuropeptides such as substance P that, by degranulating mast cells, might promote renin release, thus activating a local RAS and ultimately inducing cardiac dysfunction. We tested this hypothesis in whole hearts ex vivo, in cardiac nerve terminals in vitro, and in cultured mast cells.

Abeta peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis.

Cerebral amyloid angiopathy (CAA) caused by amyloid beta (Abeta) deposition around brain microvessels results in vascular degenerative changes. Antiangiogenic Abeta properties are known to contribute to the compromised cerebrovascular architecture. Here we hypothesize that Abeta peptides impair angiogenesis by causing endothelial cells to enter senescence at an early stage of vascular development.

Dutch and Arctic mutant peptides of beta amyloid(1-40) differentially affect the FGF-2 pathway in brain endothelium.

Single point mutations of the amyloid precursor protein generate Abeta variants bearing amino acid substitutions at positions 21-23. These mutants are associated with distinct hereditary phenotypes of cerebral amyloid angiopathy, manifesting varying degrees of tropism for brain vessels, and impaired microvessel remodeling and angiogenesis. We examined the differential effects of E22Q (Dutch), and E22G (Arctic) variants in comparison to WT Abeta on brain endothelial cell proliferation, angiogenic phenotype expression triggered by fibroblast growth factor (FGF-2), pseudo-capillary sprouting, and induction of apoptosis.

Molecular basis of branched peptides resistance to enzyme proteolysis.

We found that synthetic peptides in the form of dendrimers become resistant to proteolysis. To determine the molecular basis of this resistance, different bioactive peptides were synthesized in monomeric, two-branched and tetra-branched form and incubated with human plasma and serum. Proteolytic resistance of branched multimeric sequences was compared to that of the same peptides synthesized as multimeric linear molecules.