Extracellular matrix, gap junctions, and retinal vascular homeostasis in diabetic retinopathy

doi:10.1016/j.exer.2014.08.011

Experimental Eye Research

Volume 133, April 2015, Pages 58-68

https://doi.org/10.1016/j.exer.2014.08.011 Get rights and content

Highlights

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Effects of vascular basement membrane changes in diabetic retinopathy.
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Overexpression of ECM components contributes to retinal vascular BM thickening in DR.
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BM remodeling plays a critical role in angiogenesis and ultimately PDR.
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ECM changes promote disturbed retinal vascular homeostasis in DR.
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Altered cell–cell communication triggers apoptosis induces retinal vascular cell loss in DR.

Abstract

The vascular basement membrane (BM) contains extracellular matrix (ECM) proteins that assemble in a highly organized manner to form a supportive substratum for cell attachment facilitating myriad functions that are vital to cell survival and overall retinal homeostasis. The BM provides a microenvironment in which bidirectional signaling through integrins regulates cell attachment, turnover, and functionality. In diabetic retinopathy, the BM undergoes profound structural and functional changes, and recent studies have brought to light the implications of such changes. Thickened vascular BM in the retinal capillaries actively participate in the development and progression of characteristic changes associated with diabetic retinopathy. High glucose (HG)-induced compromised cell–cell communication via gap junctions (GJ) in retinal vascular cells may disrupt homeostasis in the retinal microenvironment. In this review, the role of altered ECM synthesis, compromised GJ activity, and disturbed retinal homeostasis in the development of retinal vascular lesions in diabetic retinopathy are discussed.

Section snippets

ECM structure and function

The ECM provides a mechanical framework on which cells reside, and thus contributes to the structural integrity of the retinal vasculature. It imparts functionality by serving as a substratum for cell attachment (Mao and Schwarzbauer, 2005), facilitating intercellular communication (Boudreau and Jones, 1999), and promoting wound healing (Valero et al., 2014), among other functions. ECM is a multimeric structure composed of various components, including fibronectin (FN), laminin (LM), collagen

Structural changes in the vascular BM and its relevance to diabetic retinopathy

Vascular BM thickening is the histological hallmark of diabetic retinopathy (Cherian et al., 2009, Lee et al., 2010b, Stitt et al., 1994). The retinal BM in patients with diabetic retinopathy has been described as being irregular and highly vacuolar with a “Swiss cheese”–like appearance (Powner et al., 2011). Although vascular BM thickening has been identified long ago, recent studies have brought to light its relevance to diabetic retinopathy through in vitro and in vivo experiments. The

ECM and inflammation in diabetic retinopathy

Inflammation in the diabetic retina is mediated through complex interactions involving proteases, growth factors, cytokines, and chemokines released from glial and vascular cells that ultimately compromise cellular functions (Mohammad et al., 2013). The following section addresses how inflammatory cytokines considered as “markers of inflammation” influence ECM and the pathogenesis of diabetic retinopathy.

Tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β) are inflammatory cytokines

BM and angiogenesis in diabetic retinopathy

Angiogenesis is an over compensatory pathological event seen in late-stage diabetic retinopathy after hypoxia and vascular BM thickening have already developed (Durham and Herman, 2011). BM remodeling and uncontrolled neovascularization induced by growth factors (Durham and Herman, 2011) are critical players underlying these two events. BM remodeling is a dynamic process involving the synthesis and breakdown of BM components, orchestrated primarily by the MMP and urokinase plasminogen

ECM and GJs in diabetic retinopathy

GJIC is essential for cell survival and maintenance of tissue homeostasis (Dagli and Hernandez-Blazquez, 2007, Li et al., 2012, Wei et al., 2004). Connexin channels are the primary conduits in GJs that facilitate cell–cell communication by exchange of small molecules less than 1 kD between adjacent cells (Wright et al., 2012). GJIC activity is thus vital for various cellular functions, including regulation of cell growth, differentiation, and development (Wei et al., 2004). Importantly, GJIC

Discussion

Our understanding of retinal vascular BM and its role in mediating characteristic lesions associated with diabetic retinopathy has significantly improved in the last decade. The structural changes in the vascular BM are now recognized as an active participant in the development and progression of the characteristic lesions of diabetic retinopathy. In particular, the BM regulates ECM-cell signaling, cell–cell communication, vascular cell survival, barrier characteristics, and influences the

Acknowledgments

Research was supported by NIH, NEI 018218, and in part by a departmental grant from the Massachusetts Lions Eye Research Fund to SR, and the MSSRP award to EB at Boston University School of Medicine.

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ReviewExtracellular matrix, gap junctions, and retinal vascular homeostasis in diabetic retinopathy

Highlights

Abstract

Section snippets

ECM structure and function

Structural changes in the vascular BM and its relevance to diabetic retinopathy

ECM and inflammation in diabetic retinopathy

BM and angiogenesis in diabetic retinopathy

ECM and GJs in diabetic retinopathy

Discussion

Acknowledgments

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Alterations in basement membrane immunoreactivity of the diabetic retina in three diabetic mouse models

Graefe's Arch. Clin. Exp. Ophthalmol. Albrecht von Graefes Arch. klin. Exp. Ophthalmol.

FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats

Diabetes

High-glucose-induced endothelial cell injury is inhibited by a Peptide derived from human apolipoprotein E

PloS One

Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice

Investig. Ophthalmol. Vis. Sci.

Extracellular matrix and integrin signalling: the shape of things to come

Biochem. J.

Erytrocyte membrane anionic charge in type 2 diabetic patients with retinopathy

BMC Ophthalmol.

Distribution of laminins in the developing human eye

Investig. Ophthalmol. Vis. Sci.

Effects of tenascin-C on normal and diabetic retinal endothelial cells in culture

Investig. Ophthalmol. Vis. Sci.

High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-kappa B and AP-1

Am. J. Physiol. Cell Physiol.

Tight glycemic control regulates fibronectin expression and basement membrane thickening in retinal and glomerular capillaries of diabetic rats

Investig. Ophthalmol. Vis. Sci.

High glucose increases lysyl oxidase expression and activity in retinal endothelial cells: mechanism for compromised extracellular matrix barrier function

Diabetes

High glucose-induced altered basement membrane composition and structure increases trans-endothelial permeability: implications for diabetic retinopathy

Curr. Eye Res.

Heparan sulfate proteoglycans in experimental models of diabetes: a role for perlecan in diabetes complications

Diabetes Metab. Res. Rev.

Tenascin: a multifunctional extracellular matrix protein with a restricted distribution in development and disease

J. Cell. Biochem.

Extracellular matrix-stimulated phospholipase activation is mediated by beta 1-integrin

Am. J. Physiol.

Loss of beta 1 integrin function results in upregulation of connexin expression in embryonic stem cell-derived cardiomyocytes

Int. J. Dev. Biol.

Roles of gap junctions and connexins in non-neoplastic pathological processes in which cell proliferation is involved

J. Membr. Biol.

Muller cell expression of genes implicated in proliferative vitreoretinopathy is influenced by substrate elastic modulus

Investig. Ophthalmol. Vis. Sci.

Folding of collagen IV

Eur. J. Biochem. FEBS

Microvascular modifications in diabetic retinopathy

Curr. Diabetes Rep.

ECM-induced gap junctional communication enhances mammary epithelial cell differentiation

J. Cell Sci.

Extracellular matrix in angiogenesis: dynamic structures with translational potential

Exp. Dermatol.

Aldose reductase inhibition fails to prevent retinopathy in diabetic and galactosemic dogs

Diabetes

Modes of retinal cell death in diabetic retinopathy

J. Clin. Exp. Ophthalmol.

Inhibition of advanced glycation end-products protects against retinal capillary basement membrane expansion during long-term diabetes

J. Pathol.

Review
Extracellular matrix, gap junctions, and retinal vascular homeostasis in diabetic retinopathy