Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

Abstract

The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies.

Silymarin reduces retinal microvascular damage in streptozotocin-induced diabetic rats

“…Previous studies also disclosed that hyperglycemia provoked the expression of extracellular matrix molecules in retinal epithelial cells 65 , 66 . Qin et al manifested that hyperglycemia promoted fibronectin and collagen IV expression in human retinal epithelial cells 67 .…”

“…Qin et al manifested that hyperglycemia promoted fibronectin and collagen IV expression in human retinal epithelial cells 67 . Increased deposition of extracellular matrix proteins is considered a hallmark of diabetic retinopathy 65 . Several studies documented that TGF-β is implicated in the pathogenesis of diabetic retinopathy via disrupting angiogenesis and BRB and increasing the accumulation of extracellular matrix proteins 67 , 68 .…”

The role of inflammation and neurodegeneration in diabetic macular edema

“…8 The retinal capillaries are enveloped by pericytes, which maintain the integrity of the inner BRB, and an extracellular matrix known as endothelial basement membrane (EBM), which provides mechanical stability and interaction between endothelial cells and pericytes. [9][10][11] The pericytes regulate the blood flow and secrete inflammatory mediators promoting immune cells adhesion, extravasation, and migration into the extracellular matrix. 12 The pericytes express the major histocompatibility complex (MHC) class 1; they can express MHC class II in selected circumstances, supporting their role as antigen-presenting cells.…”

Complement 3a Mediates CCN2/CTGF in Human Retinal Pigment Epithelial Cells

“…These retinal vasculopathies are multifactorial and caused by the combination of hypoxic stress, inflammatory response, and endothelial and extracellular matrix (ECM) dysfunction [ 3 ]. ECM acts as an essential support, regulating the scaffold of retinal development and vascular pathologies [ 4 ]. One major profibrotic factor that promotes excessive ECM accumulation is cellular communication network 2 (CCN2), also known as connective tissue growth factor (CTGF), which is essential for vascular development and the modulation of cell movement [ 5 ].…”