Cysteine‐rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy

Abstract

The vasculature forms a highly branched network investing every organ of vertebrate organisms. The retinal circulation, in particular, is supported by a central retinal artery branching into superficial arteries, which dive into the retina to form a dense network of capillaries in the deeper retinal layers. The function of the retina is highly dependent on the integrity and proper functioning of its vascular network and numerous ocular diseases including diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity are caused by vascular abnormalities culminating in total and sometimes irreversible loss of vision. CCN1 and CCN2 are inducible extracellular matrix (ECM) proteins which play a major role in normal and aberrant formation of blood vessels as their expression is associated with developmental and pathological angiogenesis. Both CCN1 and CCN2 achieve disparate cell-type and context-dependent activities through modulation of the angiogenic and synthetic phenotype of vascular and mesenchymal cells respectively. At the molecular level, CCN1 and CCN2 may control capillary growth and vascular cell differentiation by altering the composition or function of the constitutive ECM proteins, potentiating or interfering with the activity of various ligands and/or their receptors, physically interfering with the ECM-cell surface interconnections, and/or reprogramming gene expression driving cells toward new phenotypes. As such, these proteins emerged as important prognostic markers and potential therapeutic targets in neovascular and fibrovascular diseases of the eye. The purpose of this review is to highlight our current knowledge and understanding of the most recent data linking CCN1 and CCN2 signaling to ocular neovascularization bolstering the potential value of targeting these proteins in a therapeutic context.

The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling

“…Studies aimed at unraveling the effects of specific ECM proteins on the behavior of ECs and the shaping of the vascular network could conceivably identify new therapeutic targets in the ECM and substantially improve existing tools for clinical use in angiogenesisdriven diseases, including the preponderant neovascular diseases of the retina (Yan and Chaqour, 2013). Here, we show that CCN1 is largely expressed by retinal angiogenic ECs at the forefront of the growing vascular network during sprouting angiogenesis.…”

A Perspective on the Role of the Extracellular Matrix in Progressive Retinal Degenerative Disorders

“…The role of the ECM in the abnormal neovascularization associated with DR is better explored than the role of the ECM in PIRDDs, thus illuminating potential ECM drug targets such as connective tissue growth factor (CTGF). 36 A secreted protein, CTGF induces ECM production and angiogenesis during DR, and intravitreal delivery of siRNA targeted to CTGF was shown to result in decreased expression of a specific subset of ECM proteins. 37 Subsequent results to evaluate the therapeutic impact of this ECM modulation (e.g., to determine whether neovascularization or DR progression is affected) will be eagerly awaited.…”

Degradome Products of the Matricellular Protein CCN1 as Modulators of Pathological Angiogenesis in the Retina

“…Analyses of fluids and tissue biopsies from human clinical specimens have shown increased levels of CCN1 in several ocular vascular complications, including proliferative diabetic retinopathy (PDR) and active ophthalmopathy (11,12). Similarly, the levels of CCN1 increased in retinal blood vessels at the early stages of diabetes and in late stages of proliferative disorders in mouse models of diabetic and ischemic angiopathies (13,14).…”