Abstract
Significantly reduced levels of the anti-inflammatory gaseous transmitter hydrogen sulfide (H2S) are observed in diabetic patients and correlate with microvascular dysfunction. H2S may protect the microvasculature by preventing loss of the endothelial glycocalyx. We tested the hypothesis that H2S could prevent or treat retinal microvascular endothelial dysfunction in diabetes. Bovine retinal endothelial cells (BRECs) were exposed to normal (NG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) ± the slow-release H2S donor NaGYY4137 in vitro. Glycocalyx coverage (stained with WGA-FITC) and calcein-labeled monocyte adherence were measured. In vivo, fundus fluorescein angiography (FFA) was performed in normal and streptozotocin-induced (STZ) diabetic rats. Animals received intraocular injection of NaGYY4137 (1 μM) or the mitochondrial-targeted H2S donor AP39 (100 nM) simultaneously with STZ (prevention) or on day 6 after STZ (treatment), and the ratio of interstitial to vascular fluorescence was used to estimate apparent permeability. NaGYY4137 prevented HG-induced loss of BREC glycocalyx, increased monocyte binding to BRECs (p ≤ 0.001), and increased overall glycocalyx coverage (p ≤ 0.001). In rats, the STZ-induced increase in apparent retinal vascular permeability (p ≤ 0.01) was significantly prevented by pre-treatment with NaGYY4137 and AP39 (p < 0.05) and stabilized by their post-STZ administration. NaGYY4137 also reduced the number of acellular capillaries (collagen IV + /IB4-) in the diabetic retina in both groups (p ≤ 0.05). We conclude that NaGYY4137 and AP39 protected the retinal glycocalyx and endothelial permeability barrier from diabetes-associated loss of integrity and reduced the progression of diabetic retinopathy (DR). Hydrogen sulfide donors that target the glycocalyx may therefore be a therapeutic candidate for DR.
Highlights
Loss of integrity of the vascular permeability barrier is associated with a range of pathological conditions
We investigated the effects of a single dose of two slow-release H2S donor molecules, the cytosolic sodium GYY4137 (Li et al, 2008) and the mitochondria-specific sulfide donor AP39 (Le Trionnaire et al, 2014), on retinal vascular permeability in vivo in the Norway Brown rat streptozotocin-induced diabetic retinopathy (DR) model
Two hydrogen sulfide generating molecules were investigated, NaGYY4137 and AP39. The former is a slow-releasing hydrogen sulfide donor (Alexander et al, 2015) that does not target any specific part of the cell, whereas AP39 is a mitochondrial targeted donor (Le Trionnaire et al, 2014)
Summary
Loss of integrity of the vascular permeability barrier is associated with a range of pathological conditions. The vascular permeability barrier is formed of endothelial cells (ECs), their underlying basement membrane, and the endothelial glycocalyx. The latter is recognized as a key regulator of permeability as demonstrated by a range of studies showing that selective loss of specific glycocalyx components is associated with altered permeability properties in various vascular beds (Jeansson and Haraldsson, 2003; Singh et al, 2007; Landsverk et al, 2012; Betteridge et al, 2017; Onions et al, 2019). Strategies to reverse or reduce glycocalyx damage in diabetes have the potential to rescue some of the potentially damaging vascular changes that underlie the development of vascular complications such as retinopathy
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