A CTGF-YAP Regulatory Pathway Is Essential for Angiogenesis and Barriergenesis in the Retina
Sohyun Moon,
Sangmi Lee,
Joy Ann Caesar,
Sarah Pruchenko,
Andrew Leask,
James A. Knowles,
Jose Sinon,
Brahim Chaqour
Affiliations
Sohyun Moon
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
Sangmi Lee
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
Joy Ann Caesar
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
Sarah Pruchenko
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
Andrew Leask
University of Saskatchewan, College of Dentistry, E3338 HS - 105 Wiggins Road, Saskatoon, SK S7N 5E4, Canada
James A. Knowles
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
Jose Sinon
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
Brahim Chaqour
State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA; State University of New York, Downstate Health Science University, Department of Ophthalmology, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; SUNY Eye Institute, SUNY Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Corresponding author
Summary: Connective tissue growth factor (CTGF) or cellular communication network 2 (CCN2) is a matricellular protein essential for normal embryonic development and tissue repair. CTGF exhibits cell- and context-dependent activities, but CTGF function in vascular development and barrier function is unknown. We show that endothelial cells (ECs) are one of the major cellular sources of CTGF in the developing and adult retinal vasculature. Mice lacking CTGF expression either globally or specifically in ECs exhibit impaired vascular cell growth and morphogenesis and blood barrier breakdown. The global molecular signature of CTGF includes cytoskeletal and extracellular matrix protein, growth factor, and transcriptional co-regulator genes such as yes-associated protein (YAP). YAP, itself a transcriptional activator of CTGF, mediates several CTGF-controlled angiogenic and barriergenic transcriptional programs. Re-expression of YAP rescues, at least partially, angiogenesis and barriergenesis in CTGF mutant mouse retinas. Thus, the CTGF-YAP regulatory loop is integral to retinal vascular development and barrier function.
