Diabetes-induced morphological, biomechanical, and compositional changes in ocular basement membranes

To, Margaret Q; Goz, Alexandra; Camenzind, Leon C.; Oertle, Philipp; Candiello, Joseph; Sullivan, Mara; Henrich, P. B.; Loparić, Marko; Safi, Farhad; Eller, Andrew W.; Halfter, Willi

doi:10.1016/j.exer.2013.09.011

Cited by 59 publications

(77 citation statements)

References 44 publications

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“…The AFM‐based thickness values were by a factor of two greater than the TEM thickness measurements (Fig. H) . In addition, the AFM data have confirmed the age‐related increase in BM thickness.…”

Section: New Data On Bm Biologysupporting

confidence: 58%

New concepts in basement membrane biology

et al. 2015

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Basement membranes (BMs) are thin sheets of extracellular matrix that outline epithelia, muscle fibers, blood vessels and peripheral nerves. The current view of BM structure and functions is based mainly on transmission electron microscopy imaging, in vitro protein binding assays, and phenotype analysis of human patients, mutant mice and invertebrata. Recently, MS-based protein analysis, biomechanical testing and cell adhesion assays with in vivo derived BMs have led to new and unexpected insights. Proteomic analysis combined with ultrastructural studies showed that many BMs undergo compositional and structural changes with advancing age. Atomic force microscopy measurements in combination with phenotype analysis have revealed an altered mechanical stiffness that correlates with specific BM pathologies in mutant mice and human patients. Atomic force microscopy-based height measurements strongly suggest that BMs are more than two-fold thicker than previously estimated, providing greater freedom for modelling the large protein polymers within BMs. In addition, data gathered using BMs extracted from mutant mice showed that laminin has a crucial role in BM stability. Finally, recent evidence demonstrate that BMs are bi-functionally organized, leading to the proposition that BM-sidedness contributes to the alternating epithelial and stromal tissue arrangements that are found in all metazoan species. We propose that BMs are ancient structures with tissue-organizing functions and were essential in the evolution of metazoan species.Abbreviations AFM, atomic force microscopy; BM, basement membrane; DN, Descemet's membrane; ECM, extracellular matrix; HSPG, heparan sulfate proteoglycan; ILM, inner limiting membrane; LC, lens capsule; TEM, transmission electron microscopy.

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Section: New Data On Bm Biologysupporting

confidence: 58%

New concepts in basement membrane biology

et al. 2015

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“…This observation agrees well with past reports of increased BM collagen IV accumulation in retinal vessels of diabetic rats and humans with DR (7, 37‐39). Other BM components, such as fibronectin, tenascin‐C, and collagen XIII, are also deposited in excessive amounts in diabetic retinal capillary BMs (38–40). Among these, fibronectin is particularly important as it interacts with both collagen IV and LOX via specific molecular domains within its N‐ and C‐terminal domains, respectively (22, 41), and is implicated in regulating LOX activity (22).…”

Section: Discussionmentioning

confidence: 99%

Basement membrane stiffening promotes retinal endothelial activation associated with diabetes

Yang

Scott

Monickaraj³

et al. 2015

FASEB j.

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Endothelial activation is a hallmark of the high-glucose (HG)-induced retinal inflammation associated with diabetic retinopathy (DR). However, precisely how HG induces retinal endothelial activation is not fully understood. We hypothesized that HG-induced upregulation of lysyl oxidase (LOX), a collagen-cross-linking enzyme, in retinal capillary endothelial cells (ECs) enhances subendothelial basement membrane (BM) stiffness, which, in turn, promotes retinal EC activation. Diabetic C57BL/6 mice exhibiting a 70 and 50% increase in retinal intercellular adhesion molecule (ICAM)-1 expression and leukocyte accumulation, respectively, demonstrated a 2-fold increase in the levels of BM collagen IV and LOX, key determinants of capillary BM stiffness. Using atomic force microscopy, we confirmed that HG significantly enhances LOX-dependent subendothelial matrix stiffness in vitro, which correlated with an ∼2.5-fold increase in endothelial ICAM-1 expression, a 4-fold greater monocyte-EC adhesion, and an ∼2-fold alteration in endothelial NO (decrease) and NF-kB activation (increase). Inhibition of LOX-dependent subendothelial matrix stiffening alone suppressed HG-induced retinal EC activation. Finally, using synthetic matrices of tunable stiffness, we demonstrated that subendothelial matrix stiffening is necessary and sufficient to promote EC activation. These findings implicate BM stiffening as a critical determinant of HG-induced retinal EC activation and provide a rationale for examining BM stiffness and underlying mechanotransduction pathways as therapeutic targets for diabetic

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“…Parallel changes have been found in a mouse model presenting retinal abnormalities (Hu et al, 2010). Retinal BM has been found to undergo substantial changes in disease states such as diabetes and retinal ectopias (Hu et al, 2010; To et al, 2013). The BM of the TM has yet to be subjected to such systematic rigorous studies.…”

Section: Basement Membranes and Their Componentsmentioning

confidence: 99%

Segmental outflow of aqueous humor in mouse and human

Carreon

Edwards

Wang

et al. 2017

Experimental Eye Research

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The main and only modifiable risk factor in glaucoma, the group of usually late onset progressive and irreversible blinding optic neuropathies, is elevated intraocular pressure (IOP). The increase in IOP is due to impeded aqueous humor (AH) outflow through the conventional pathway. The aberrant increased resistance at the trabecular meshwork (TM), the filter-like region in the anterior eye chamber is the major contributory factor in causing the impeded outflow. In normal as well as in glaucoma eyes the regions of the TM are divided into areas of high and low flow. The collector channels and distal outflow regions are now increasingly being recognized as potential players in contributing to impede AH outflow. Structural and molecular make-up contributing to the segmental blockage to outflow is likely to provide greater insight. Establishing segmental blockage to outflow in model systems of glaucoma such as the mouse in parallel to human eyes will expand our repertoire of tools for investigation. Further study into this area of interest has the potential to ultimately lead to the development of new therapeutics focused on lowering IOP by targeting the various components of segmental blockage of outflow in the TM and in the distal outflow region.

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Diabetes-induced morphological, biomechanical, and compositional changes in ocular basement membranes

Cited by 59 publications

References 44 publications

New concepts in basement membrane biology

New concepts in basement membrane biology

Basement membrane stiffening promotes retinal endothelial activation associated with diabetes

Segmental outflow of aqueous humor in mouse and human

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