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.
Highlights
The hallmark of many forms of blinding diseases is a disrupted oxygen supply to the neural retina and subsequent loss of function of photosensitive neurons required for photo-transduction and transmission of visual information from the retina to visual processing and cognitive centers in the brain [1,2]
The data discussed in this paper clearly indicate that the vascular matrix is a determining factor of vascular growth, morphogenesis and barrier function during blood vessel development and regeneration and that qualitative and/or quantitative alterations of components of the vascular matrisome have dramatic pathophysiological consequences on retinal health and function
It is becoming clear that subendothelial matrix components, those of the matricellular protein family (e.g., CCN2/CTGF), do not subserve a structural role in the vascular wall, they are critical for proper tissue vascularization and cellular adaptational responses to chemical and physical challenges
Summary
The hallmark of many forms of blinding diseases is a disrupted oxygen supply to the neural retina and subsequent loss of function of photosensitive neurons required for photo-transduction and transmission of visual information from the retina to visual processing and cognitive centers in the brain [1,2]. The ensuing discordance between vascular supply and tissue demand for oxygen and nutrients produces severe hypoxia and the mounting of a hypoxic response that causes detrimental preretinal and intravitreal neovascularization. This secondary angiogenesis is well characterized as a fundamental pathological feature of proliferative DR and stage II ROP, because it does not allow a normal revascularization of the ischemic retina despite a strong hypoxic response that culminates in enhanced production of proangiogenic factors [17,18]. The interested reader is referred to review articles describing other aspects of the ocular ECM and its relevance in different biological and clinical settings [35,36,37]
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