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.

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…Also, in contrast to previous xenograft results with FG-3019 that demonstrated antitumor activity (41,42), treatment with FG-3019 alone did not result in significant antitumoral responses in KPC mice. Previous reports have also described CTGF as a critical mediator of vascular remodeling by regulating pericyte function and endothelial basement membrane formation during angiogenesis (43). In the tumor microenvironment, CTGF and the CXCR2 chemokine ligand axis have also been implicated as promoters of tumor angiogenesis in a variety of PDA models (42,44).…”

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

“…At the cellular level this response involves endothelial sprouting via CCN1 (CYR61) 29 and maturation-that is, pericyte investment-via CCN2 (CTGF) 24 resulting in a stable and functional vascular network that can carry collateral blood flow and improve conductance. Pericyte investment is crucial herein since Ang 2, by virtue of disrupting pericyte investment 38 , abolished the positive effects exerted by T 4-MRTF signalling (Fig.…”

“…1f) 28 . Both, MRTF-A and T 4, induced expression of genes involved in microvessel growth, most notably CCN1, mediating angiogenesis 29 and CCN2, relevant for 10T1/2 pericyte-like cell attraction 24 ( Supplementary Fig. 1c-g).…”

“…Since T 4 is a potent pro-angiogenic factor 21 , an involvement of the T 4-MRTF-SRF axis in vascular growth would require transcriptional activation beyond well-known myogenic proteins 13,14 . However, MRTF coactivaton of SRF induces pro-angiogenic factors such as CCN1 (Cyr61) 22 and maturation factors such as connective tissue growth factor (CTGF) 23,24 . Moreover, SRF controls tip cell behaviour in angiogenesis 25,26 , indicating a role of MRTF-SRF in vascular growth and maintenance.…”

Emerging roles of CCN proteins in vascular development and pathology

“…Vascular defects in the CCN1 null mouse appear toward the later stages of embryonic development (Hall-Glenn et al 2012) with VSMC dysregulation in size and placement as well as defects within the composition of the ECM. In adulthood, expression of CCN2 is low or absent in most tissues, yet can be rapidly upregulated after vascular injury or in sustained disease states, such as atherosclerosis.…”