Disorders of retinal vessel growth and barrier dysfunction are responsible for vision loss in ischemic retinopathy (IR), a set of clinically well-defined chronic ocular vascular complications causing vision impairment and blindness in all age groups. Elucidation of the molecular bases of angiogenic cell function and behavior in physiological and pathological conditions will have important therapeutic implications in the treatment of IR in humans. Herein, our objectives are to gain new insights into the function and mechanisms whereby connective tissue growth factor (CTGF aka CCN2), a specific component of the vascular extracellular matrix (ECM), orchestrates the execution of angiogenesis and barriergenesis programs during retinal vascular development and pathology. CTGF is a developmentally-regulated fetal gene predominantly expressed in endothelial cells (ECs) and pericytes of the retinal vasculature. CTGF expression is rapidly induced in vascular endothelial growth factor (VEGF)-stimulated ECs in culture and substantially increased in VEGF-induced retinal neovascularization models in vivo although the functional consequences of CTGF signaling are unknown. Structurally, the CTGF protein contains modular domains that bind directly to integrin receptors and/or moieties in the pericellular environment including VEGF and matrix metalloproteinase (MMP)-2. Our data showed that CTGF-deficiency was coupled to severe vascular abnormalities and a breach of vascular barrier function in the retina during development. Morphological and molecular evidence of cytoskeletal alterations in retinal vascular cells was associated with CTGF-deficiency as well. It is our hypothesis that CTGF, regulates, through its interactomic network, actin cytoskeleton dynamics that are critical in various steps of angiogenesis and barriergenesis. We further postulate that dysregulation of the CTGF interactomic networks under ischemic conditions alters vasogenic factor activity, availability and structure, ultimately leading to aberrant angiogenic and permeability responses. We will test these hypotheses in the following specific Aims:
Aim 1 will define the cell type-specific CTGF signals, the associated cytoskeletal remodeling and the changes driving retinal vessel growth and morphogenesis.
Aim 2 will determine the relative contribution of EC- and pericyte-derived CTGF to barriergenesis, and elucidate the mechanisms whereby CTGF signals contribute to the formation and stabilization of EC-EC junctional complexes to insure cellular cohesion and barrier function.
Aim 3 will determine how CTGF-induced cytoskeletal changes, or lack thereof, contribute to development and/or progression of aberrant angiogenesis and vascular hyperpermeability in established in vivo models of vascular diseases of the eye. In these studies, greater emphasis will be placed on how CTGF interactomic and degradomic networks determine the angiogenic outcome and barrier function or dysfunction under ischemic conditions. Our studies will provide new information of considerable scientific and therapeutic interest in the treatment of IR.
Abnormal growth of blood vessels and breach of the blood retinal barrier are the hallmarks of ischemic retinopathy, a set of clinically well-defined vascular diseases (e.g., retinopathy of prematurity, macular edema, diabetic retinopathy, retinal vein occlusion, neovascular glaucoma) that affect all age groups and cause retinal detachment, edema and vision loss. Our project seeks to obtain a better understanding of the function and mechanisms of action of a specific component of the extracellular matrix, the connective tissue growth factor, considered as a potential diagnostic marker and therapeutic target in neovascular diseases of the eye. Knowledge gained from molecular and preclinical studies of how this molecule regulates normal and abnormal vessel formation, regeneration and retinal barrier function could improve the pharmacotherapy of ischemic retinopathy that was identified by the World Health Organization as a priority eye disease with respect to the prevention of blindness and visual impairment.
| Chaqour, Julienne; Lee, Sangmi; Ravichandra, Aashreya et al. (2018) Abscisic acid - an anti-angiogenic phytohormone that modulates the phenotypical plasticity of endothelial cells and macrophages. J Cell Sci 131: |
