Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy

Sangmi Lee, Menna Elaskandrany, Lester F. Lau, Douglas Lazzaro, Maria B. Grant, Brahim Chaqour

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

CYR61-CTGF-NOV (CCN)1 is a dynamically expressed extracellular matrix (ECM) protein with critical functions in cardiovascular development and tissue repair. Angiogenic endothelial cells (ECs) are a major cellular source of CCN1 which, once secreted, associates with the ECM and the cell surface and tightly controls the bidirectional flow of information between cells and the surrounding matrix. Endothelium-specific CCN1 deletion in mice using a cre/lox strategy induces EC hyperplasia and causes blood vessels to coalesce into large flat hyperplastic sinuses with no distinctive hierarchical organization. This is consistent with the role of CCN1 as a negative feedback regulator of vascular endothelial growth factor (VEGF) receptor activation. In the mouse model of oxygen-induced retinopathy (OIR), pericytes become the predominant CCN1 producing cells. Pericyte-specific deletion of CCN1 significantly decreases pathological retinal neovascularization following OIR. CCN1 induces the expression of the non-canonical Wnt5a in pericyte but not in EC cultures. In turn, exogenous Wnt5a inhibits CCN1 gene expression, induces EC proliferation and increases hypersprouting. Concordantly, treatment of mice with TNP470, a non-canonical Wnt5a inhibitor, reestablishes endothelial expression of CCN1 and significantly decreases pathological neovascular growth in OIR. Our data highlight the significance of CCN1-EC and CCN1-pericyte communication signals in driving physiological and pathological angiogenesis.

Original languageEnglish (US)
Article number1405
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Pericytes
Endothelial Cells
Pathologic Neovascularization
Oxygen
Physiologic Neovascularization
Retinal Neovascularization
Vascular Endothelial Growth Factor Receptor
Extracellular Matrix Proteins
Endothelium
Hyperplasia
Extracellular Matrix
Blood Vessels
Cell Culture Techniques
Communication
Cell Proliferation
Gene Expression
Growth

ASJC Scopus subject areas

  • General

Cite this

Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy. / Lee, Sangmi; Elaskandrany, Menna; Lau, Lester F.; Lazzaro, Douglas; Grant, Maria B.; Chaqour, Brahim.

In: Scientific Reports, Vol. 7, No. 1, 1405, 01.12.2017.

Research output: Contribution to journalArticle

Lee, Sangmi ; Elaskandrany, Menna ; Lau, Lester F. ; Lazzaro, Douglas ; Grant, Maria B. ; Chaqour, Brahim. / Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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