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Aims/hypothesis Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties. Methods Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TERalb) and hyaluronan catabolism were assessed as measures of vascular permeability. Results Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TERalb was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p < 0.05). In line, a trend towards TERalb normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group. Conclusion/interpretation Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk. Trial registration www.trialregister.nl NTR780/http://isrctn.org ISRCTN82695186 Funding An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037)

Angiogenesis is essential for tissue growth and repair, but its dysregulation is associated with various pathological conditions, such as cancer and ischemic disease. Non-neuronal [alpha]7-nicotinic acetylcholine receptors ([alpha]7-nAChRs) mediate angiogenic pathways. Activation of these receptors increases endothelial [Ca.sup.2+] concentration and stimulates intracellular signaling cascades involved in angiogenesis. The development of positive allosteric modulators and synthetic agonists targeting [alpha]7-nAChRs may serve as a strategy to enhance angiogenesis. The synthetic isoxazole compound ISO-1 acts as an [alpha]7-nAChR agonist, increasing endothelial [Ca.sup.2+] concentrations. The aim of the present study was to evaluate the potential of ISO-1 to stimulate angiogenesis in vitro. HUVECs were isolated from umbilical cords. Cell viability, proliferation, migration and angiogenic capacity were assessed using MTS, neutral red, SRB, wound healing, and tube formation assays under treatment with ISO-1 and controls. ISO-1, at concentrations ranging from 1x[10.sup.-9] to [10.sup.-3.5] M, did not affect endothelial viability. Regarding angiogenesis, ISO-1 did not stimulate endothelial cell proliferation but induced endothelial cell migration at concentrations of [10.sup.-6] and [10.sup.-4] M. This pro-migratory effect was similar to that observed with the activation of nAChRs by nicotine and choline. Furthermore, the effect was completely inhibited by the [alpha]7-nAChR antagonist [alpha]-bungarotoxin. ISO-1 increased tubular length and branching, similar to the effect of nicotine. These findings demonstrated that the isoxazole compound ISO-1, through activation of [alpha]7-nAChR, increased endothelial [Ca.sup.2+] concentration and promoted endothelial cell migration and tubular formation, two key stages of angiogenesis. Altogether, these findings suggest that ISO-1 may represent a promising therapeutic candidate for diseases characterized by impaired angiogenesis. However, further investigations are needed to elucidate its precise downstream signaling pathways and in vivo efficacy. Key words: angiogenesis, endothelial cell, [alpha]7-nAChR, isoxazole compound, HUVEC

PurposeOne of latest surgical development of preloaded Descemet membrane endothelial keratoplasty (DMEK) is the delivery of the graft with the endothelium inwards, which allows for a very fast operation, but requires a pull-through surgical technique. Although the tri-folded, endo-in DMEK technique has significant advantages, the absence of proper surgical instruments that could allow their use without the ‘pull-through’ technique still restricts the wide use of such an operation. None of the available commercial DMEK injectors could be used for tri-folded DMEK (endothelium-inward) orientation, as it requires the graft to be intently secured within the injector. This report presents a retrospective eye bank validation study of an asymmetrical injector designed to orientally implant a tri-folded DMEK graft without needing a pull-through technique.MethodsThe injector is made from transparent plastic, allowing microscopic tissue validation directly before injection. The device is asymmetrical, so the orientation of the graft can be controlled and validated according to the best eye bank practice, which is critical for successful tri-folded DMEK graft clinical application. Four different designs of the internal compartment of the injectors were evaluated with DMEK tissues. Mates from two pairs were tested on each device type, totaling 16 grafts, all loaded with folded, endo-in grafts. The tissue was prepared, loaded into the injector, and ejected to imitate the tissue manipulation in DMEK operation.ResultsAfter graft loading the delivery of the endothelium-in grafts was performed by injection, without the need for a pull-through technique. One graft (6.25%) has double-scrolled (changed its folding) within the injector with a larger (1.5 mm) internal compartment. The loss of valuable cells was between 3-23% (13.98% average). No significant differences in cell loss were observed between injectors with different internal compartment sizes. Higher viability loss (17.3% +/- 5.7) was observed for the grafts with >20 days death to prep-days in comparison with grafts stored with less than two weeks (10.9% +/-2.1).ConclusionThe TissueGUARD injector is the only injector that currently allows oriented, tri-folded DMEK injection without the need for a pull-through technique. The average cell loss after loading and ejection was 13.98%, which is comparable/better than the current best practice with the precut-preloaded technique of naturally folded DMEK.

The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 + T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 + T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities. Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

The vascular endothelium plays a vital role during embryogenesis and aging and is a cell monolayer that lines the blood vessels. The immune system recognizes the endothelium as its own. Therefore, an abnormality of the endothelium exposes the tissues to the immune system and provokes inflammation and vascular diseases such as atherosclerosis. Its secretory role allows it to release vasoconstrictors and vasorelaxants as well as cardio-modulatory factors that maintain the proper functioning of the circulatory system. The sealing of the monolayer provided by adhesion molecules plays an important role in cardiovascular physiology and pathology.