title: CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis.
abstract: CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Faith
authors.initials: F
authors.lastname: Hall-Glenn
authors.forename: R Andrea
authors.initials: RA
authors.lastname: De Young
authors.forename: Bau-Lin
authors.initials: BL
authors.lastname: Huang
authors.forename: Ben
authors.initials: B
authors.lastname: van Handel
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hofmann
authors.forename: Tom T
authors.initials: TT
authors.lastname: Chen
authors.forename: Aaron
authors.initials: A
authors.lastname: Choi
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Ong
authors.forename: Paul D
authors.initials: PD
authors.lastname: Benya
authors.forename: Hanna
authors.initials: H
authors.lastname: Mikkola
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lyons
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001808:Blood Vessels / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002450:Cell Communication; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010982:Platelet-Derived Growth Factor; D055513:Connective Tissue Growth Factor