The matricellular protein cysteine-rich protein 61 (CCN1/Cyr61) enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy

Adeel Hasan, Nataliya Pokeza, Lynn Shaw, Hyun Seung Lee, Douglas Lazzaro, Hemabindu Chintala, Daniel Rosenbaum, Maria B. Grant, Brahim Chaqour

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9542-9554
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number11
DOIs
StatePublished - Mar 18 2011
Externally publishedYes

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Cysteine-Rich Protein 61
Pathologic Neovascularization
Physiological Adaptation
Retinal Vessels
Retinopathy of Prematurity
Hematopoietic Stem Cells
Stem cells
Hyperoxia
Ischemia
Oxygen
Proteins
Lentivirus
Wnt Signaling Pathway
Cell adhesion
Endothelial cells
Blindness
Cell Adhesion
Integrins
Modulators
Cell Movement

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The matricellular protein cysteine-rich protein 61 (CCN1/Cyr61) enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy. / Hasan, Adeel; Pokeza, Nataliya; Shaw, Lynn; Lee, Hyun Seung; Lazzaro, Douglas; Chintala, Hemabindu; Rosenbaum, Daniel; Grant, Maria B.; Chaqour, Brahim.

In: Journal of Biological Chemistry, Vol. 286, No. 11, 18.03.2011, p. 9542-9554.

Research output: Contribution to journalArticle

Hasan, Adeel ; Pokeza, Nataliya ; Shaw, Lynn ; Lee, Hyun Seung ; Lazzaro, Douglas ; Chintala, Hemabindu ; Rosenbaum, Daniel ; Grant, Maria B. ; Chaqour, Brahim. / The matricellular protein cysteine-rich protein 61 (CCN1/Cyr61) enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 11. pp. 9542-9554.
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AU - Lee, Hyun Seung

AU - Lazzaro, Douglas

AU - Chintala, Hemabindu

AU - Rosenbaum, Daniel

AU - Grant, Maria B.

AU - Chaqour, Brahim

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