The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy
Open accessAbstract
Retinal vascular damages are the cardinal hallmarks of retinopathy of prematurity (ROP), a leading cause of vision impairment and blindness in childhood. Both angiogenesis and vasculogenesis are disrupted in the hyperoxia-induced vaso-obliteration phase, and recapitulated, although aberrantly, in the subsequent ischemia-induced neovessel formation phase of ROP. Yet, whereas the histopathological features of ROP are well characterized, many key modulators with a therapeutic potential remain unknown. The CCN1 protein also known as cysteine-rich protein 61 (Cyr61) is a dynamically expressed, matricellular protein required for proper angiogenesis and vasculogenesis during development. The expression of CCN1 becomes abnormally reduced during the hyperoxic and ischemic phases of ROP modeled in the mouse eye with oxygen-induced retinopathy (OIR). Lentivirus-mediated re-expression of CCN1 enhanced physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological angiogenesis following ischemia. Remarkably, injection into the vitreous of OIR mice of hematopoietic stem cells (HSCs) engineered to express CCN1 harnessed ischemia-induced neovessel outgrowth without adversely affecting the physiological adaptation of retinal vessels to hyperoxia. In vitro exposure of HSCs to recombinant CCN1 induced integrin-dependent cell adhesion, migration, and expression of specific endothelial cell markers as well as many components of the Wnt signaling pathway including Wnt ligands, their receptors, inhibitors, and downstream targets. CCN1-induced Wnt signaling mediated, at least in part, adhesion and endothelial differentiation of cultured HSCs, and inhibition of Wnt signaling interfered with normalization of the retinal vasculature induced by CCN1-primed HSCs in OIR mice. These newly identified functions of CCN1 suggest its possible therapeutic utility in ischemic retinopathy.
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In a mouse model of oxygen-induced retinopathy, overexpressing CCN1 by lentiviral delivery or injecting CCN1-overexpressing hematopoietic stem cells into the vitreous humor produced significant beneficial effects in repairing damaged vasculature.
“In a mouse model of oxygen-induced retinopathy, overexpressing CCN1 by lentiviral vector delivery, or injecting CCN1-overexpressing hematopoietic stem cells into the vitreous humor, produced significant beneficial effects in repairing damaged vasculature [139].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [139]
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CCN1/CYR61: the very model of a modern matricellular protein
Lau, L. F. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0778-3 · Cited by 338 · see citing works
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- Authors
- Hasan, A., Pokeza, N., Shaw, L., Lee, H.-S., Lazzaro, D., Chintala, H., Rosenbaum, D., Grant, M. B., & Chaqour, B.
- Affiliations
- SUNY Downstate Health Sciences University (US)
- University of Florida (US)
- State University of New York (US)
- Corresponding author
- Chaqour, Brahim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 11
- Pages
- 9542-9554
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3059032
- OpenAlex
- W1964870627
- Cited by
- 39
- References
- 63
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 3
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (P30EY021721, R21EY019387, EY019387-01A1, R01EY012601)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090730)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinopathy of Prematurity Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- matricellular proteins, retinopathy of prematurity, oxygen-induced retinopathy, ischemic retinopathy, pathological neovascularization, Wnt signaling, hematopoietic stem cells, endothelial differentiation, retinal vasculature, angiogenesis, vasculogenesis
- MeSH terms
- Animals, Cell Adhesion, Disease Models, Animal, Humans, Infant, Newborn, Ischemia, Neovascularization, Pathologic, Recombinant Proteins, Retina, Retinal Vessels, Retinopathy of Prematurity, Signal Transduction, Wnt Proteins, Mice, Cysteine-Rich Protein 61
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