New Insights into the Function of the Matricellular CCN1: an Emerging Target in Proliferative Retinopathies

The eye contains highly vascularized and completely avascular cell layers in apposition to one another. Such tissue disposition/organization involves tight coordination of vascular growth and vascular arrest. In particular, retinal vascularization, which occurs during the final embryonic stages of development in humans, emerges as a result of coordinated interactions/ cross talks among astrocytes, endothelial cells and pericytes through balanced production of guidance, chemotactic, and pro-and anti-angiogenic regulatory factors. However, the entire repertoire of the key factors involved and their precise role in the process is not fully known. During postnatal life, damage to blood vessels as a result of trauma, hyperoxia, diabetes, aging, dyslipidemia, or a number of other diseases can result in arrest of vascular development, vaso-obliteration and/or vascular occlusion as in retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, as well as a large number of other eye conditions. The resulting ischemia, which rapidly impairs oxygen levels within surrounding tissue, leads to excessive aberrant compensatory blood vessel growth invading the normally avascular vitreous, eventually causing retinal detachment and blindness. The expression or lack of multiple blood-borne and/or stroma-derived cytokines and chemokines, including those of the vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and angiopoietin systems, has been implicated in dysregulation of growth, migration, adhesion and differentiation of retinal cells in retinal vascular diseases. 1,2 Interestingly, a novel signaling system with profound effects on retinal vascular development and disease has emerged from the study of a subset of extracellular matrix (ECM) proteins known as Cysteine-rich protein 61/connective tissue growth factor/Novel overexpressed (CCN). 3 CCN1/Cyr61 is the leading member of the CCN family of proteins, which also comprises CCN2/CTGF (connective tissue growth factor), CCN3/NOV (nephroblastoma overexpressed), and CCN4-6/WISP1–3 (Wnt-inducible secreted proteins). These proteins also named matricellular proteins, do not subserve a structural/physical role in the extracellular environment but mainly function as upstream regulators of the constitutively expressed ECM proteins and influence cell fate and function. 4 Overall, CCN proteins exhibit distinct tissue distribution and function but commonly have a high content and an absolute conservation of the position of 38 cysteine residues in their primary sequences. CCN1/Cyr61 and CCN2/CTGF, the most ubiquitously expressed CCN molecules, share approximately 56% amino acid sequence homology and 4 typical domains including (i) insulin-like growth factor-binding protein (IGFBP), (ii) von Willebrand factor type-C repeat (vWC), (iii) thrombospondin type-1 (TSP1), and (iv) C-terminal (CT) (Fig. 1). The overall functions of …