A CTGF-YAP Regulatory Pathway Is Essential for Angiogenesis and Barriergenesis in the Retina

Overview

Journal iScience

Publisher Cell Press

Date 2020 Jun 6

PMID 32502964

Citations 27

Authors

Sohyun Moon

Sangmi Lee

Joy Ann Caesar

Sarah Pruchenko

Andrew Leask

James A Knowles

Jose Sinon

Brahim Chaqour

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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References

Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T . Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem. 1999; 126(1):137-45. DOI: 10.1093/oxfordjournals.jbchem.a022414. View

Bernabeu M, Jones M, Nielsen J, Kruger T, Nash R, Groen D . Computer simulations reveal complex distribution of haemodynamic forces in a mouse retina model of angiogenesis. J R Soc Interface. 2014; 11(99). PMC: 4233731. DOI: 10.1098/rsif.2014.0543. View

Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov J, Tamayo P . The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2016; 1(6):417-425. PMC: 4707969. DOI: 10.1016/j.cels.2015.12.004. View

Leask A, Holmes A, Abraham D . Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep. 2002; 4(2):136-42. DOI: 10.1007/s11926-002-0009-x. View

Dean R, Butler G, Hamma-Kourbali Y, Delbe J, Brigstock D, Courty J . Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and.... Mol Cell Biol. 2007; 27(24):8454-65. PMC: 2169415. DOI: 10.1128/MCB.00821-07. View

Chaqour B, Goppelt-Struebe M . Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. FEBS J. 2006; 273(16):3639-49. DOI: 10.1111/j.1742-4658.2006.05360.x. View

Kireeva M, Latinkic B, Kolesnikova T, Chen C, Yang G, Abler A . Cyr61 and Fisp12 are both ECM-associated signaling molecules: activities, metabolism, and localization during development. Exp Cell Res. 1997; 233(1):63-77. DOI: 10.1006/excr.1997.3548. View

Liu S, Shi-Wen X, Abraham D, Leask A . CCN2 is required for bleomycin-induced skin fibrosis in mice. Arthritis Rheum. 2010; 63(1):239-46. DOI: 10.1002/art.30074. View

Gupta S, Clarkson M, Duggan J, Brady H . Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int. 2000; 58(4):1389-99. DOI: 10.1046/j.1523-1755.2000.00301.x. View

10.

Dejana E, Orsenigo F, Lampugnani M . The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. 2008; 121(Pt 13):2115-22. DOI: 10.1242/jcs.017897. View

11.

Choi H, Zhang H, Park H, Choi K, Lee H, Agrawal V . Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat Commun. 2015; 6:6943. DOI: 10.1038/ncomms7943. View

12.

Kim J, Kim Y, Kim J, Park D, Bae H, Lee D . YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest. 2017; 127(9):3441-3461. PMC: 5669570. DOI: 10.1172/JCI93825. View

13.

Bou-Gharios G, Ponticos M, Rajkumar V, Abraham D . Extra-cellular matrix in vascular networks. Cell Prolif. 2004; 37(3):207-20. PMC: 6496925. DOI: 10.1111/j.1365-2184.2004.00306.x. View

14.

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B . Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015; 17(9):1218-27. PMC: 6186417. DOI: 10.1038/ncb3216. View

15.

Wang L, Luo J, Li B, Tian X, Chen L, Huang Y . Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature. 2016; 540(7634):579-582. DOI: 10.1038/nature20602. View

16.

Chan-Ling T, Hughes S . NG2 can be used to identify arteries versus veins enabling the characterization of the different functional roles of arterioles and venules during microvascular network growth and remodeling. Microcirculation. 2005; 12(7):539-40. DOI: 10.1080/10739680500253287. View

17.

Bosma E, van Noorden C, Schlingemann R, Klaassen I . The role of plasmalemma vesicle-associated protein in pathological breakdown of blood-brain and blood-retinal barriers: potential novel therapeutic target for cerebral edema and diabetic macular edema. Fluids Barriers CNS. 2018; 15(1):24. PMC: 6146740. DOI: 10.1186/s12987-018-0109-2. View

18.

Nakajima H, Mochizuki N . Flow pattern-dependent endothelial cell responses through transcriptional regulation. Cell Cycle. 2017; 16(20):1893-1901. PMC: 5638382. DOI: 10.1080/15384101.2017.1364324. View

19.

Zhao Z, Nelson A, Betsholtz C, Zlokovic B . Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015; 163(5):1064-1078. PMC: 4655822. DOI: 10.1016/j.cell.2015.10.067. View

20.

Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N . A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 2013; 154(5):1047-1059. DOI: 10.1016/j.cell.2013.07.042. View