CYR61 (CCN1) Is Essential for Placental Development and Vascular Integrity

Abstract

CYR61 (CCN1) is a member of the CCN family of secreted matricellular proteins that includes connective tissue growth factor (CCN2), NOV (CCN3), WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6). First identified as the product of a growth factor-inducible immediate-early gene, CYR61 is an extracellular matrixassociated angiogenic inducer that functions as a ligand of integrin receptors to promote cell adhesion, migration, and proliferation. Aberrant expression of Cyr61 is associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis. To understand the functions of CYR61 during development, we have disrupted the Cyr61 gene in mice. We show here that Cyr61-null mice suffer embryonic death: ϳ30% succumbed to a failure in chorioallantoic fusion, and the reminder perished due to placental vascular insufficiency and compromised vessel integrity. These findings establish CYR61 as a novel and essential regulator of vascular development. CYR61 deficiency results in a specific defect in vessel bifurcation (nonsprouting angiogenesis) at the chorioallantoic junction, leading to an undervascularization of the placenta without affecting differentiation of the labyrinthine syncytiotrophoblasts. This unique phenotype is correlated with impaired Vegf-C expression in the allantoic mesoderm, suggesting that CYR61-regulated expression of Vegf-C plays a role in vessel bifurcation. The genetic and molecular basis of vessel bifurcation is presently unknown, and these findings provide new insight into this aspect of angiogenesis.

Identification of a Novel Integrin αvβ3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells

“…Consistent with its expression in the developing vasculature, CCN1 promotes pro-angiogenic activities upon endothelial cells in vitro and induces neovascularization in vivo (2)(3)(4). The essential role of CCN1 in vessel development has been established in gene targeting studies, as Ccn1-null mice suffer embryonic death primarily due to vascular defects in both the placenta and the embryo (5). CCN1 can also regulate a set of genes that control angiogenesis and matrix remodeling (6), suggesting that it may modulate these processes in various physiological and pathological contexts.…”

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

“…It is possible that CCN1 may be beneficial in normal wound healing and tissue repair in contexts of resolving fibrosis but contribute to fibrosis in models of progressive fibrosis. Although the bleomycin model of lung fibrosis is known to be a slowly resolving model, we attempted to test the influence of targeting CCN1 by administering siRNA during the active fibrotic phase (d [8][9][10][11][12][13][14][15][16][17][18][19][20]. Future studies should address the effects of CCN1 in preclinical animal models of progressive fibrosis.…”

“…CCN1 is an essential regulator of vascular development and CCN1-null mice suffer embryonic death due to loss of vascular integrity and impaired placental development (8). CCN1 is highly induced in granulation tissue during wound healing of the skin and activates a set of genes involved in angiogenesis, inflammation, and matrix remodeling (9).…”

Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

“…CYR61 has been implicated in carcinogenesis, wound healing and cardiovascular development through binding to integrins such as aVb3, aMb2 and a6b1 (refs [14][15][16][17]. Notably, Cyr61-deficient mice are embryonic lethal because of cardiovascular defects 18 . Depending on the cell type and context, CYR61 can promote the proliferation, survival, migration or senescence of cells 14,[17][18][19][20] .…”

“…Notably, Cyr61-deficient mice are embryonic lethal because of cardiovascular defects 18 . Depending on the cell type and context, CYR61 can promote the proliferation, survival, migration or senescence of cells 14,[17][18][19][20] . CYR61 is overexpressed in various cancer cells, including cancers of epithelial origin, and can promote their proliferation [21][22][23] .…”