Identification of integrin αMβ2 as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4457-4465 ◽  
Author(s):  
Joseph M. Schober ◽  
Ningyu Chen ◽  
Tatiana M. Grzeszkiewicz ◽  
Igor Jovanovic ◽  
Eugene E. Emeson ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Cell Surface ◽  
Tissue Growth ◽  
Early Gene ◽  
Gene Products ◽  
Monocyte Adhesion ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Atherosclerotic Lesions

Cysteine-rich 61 (Cyr61, CCN1) and connective tissue growth factor (CTGF, CCN2) are growth factor–inducible immediate-early gene products found in blood vessel walls and healing cutaneous wounds. We previously reported that the adhesion of endothelial cells, platelets, and fibroblasts to these extracellular matrix–associated proteins is mediated through integrin receptors. In this study, we demonstrated that both Cyr61 and CTGF are expressed in advanced atherosclerotic lesions of apolipoprotein E–deficient mice. Because monocyte adhesion and transmigration are important for atherosclerosis, wound healing, and inflammation, we examined the interaction of THP-1 monocytic cells and isolated peripheral blood monocytes with Cyr61 and CTGF. THP-1 cells and monocytes adhered to Cyr61- or CTGF-coated wells in an activation-dependent manner and this process was mediated primarily through integrin αMβ2. Additionally, expression of αMβ2 on human embryonic kidney 293 cells resulted in enhanced cell adhesion to Cyr61. Consistent with these data, a GST-fusion protein containing the I domain of the integrin αM subunit bound specifically to immobilized Cyr61 or CTGF. We have also investigated the requirement of cell surface heparan sulfate proteoglycans (HSPGs) as coreceptors for monocyte adhesion to Cyr61. Pretreatment of monocytes with heparin or heparinase I resulted in partial inhibition of cell adhesion to Cyr61. However, monocytes, but not fibroblasts, were capable of adhering to a Cyr61 mutant deficient in heparin binding activity. Collectively, these results show that activated monocytes adhere to Cyr61 and CTGF through integrin αMβ2 and cell surface HSPGs. However, unlike fibroblast adhesion to Cyr61, cell surface HSPGs are not absolutely required for this adhesion process.

scholarly journals CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin

2004 ◽  
Vol 15 (12) ◽  
pp. 5635-5646 ◽  
Author(s):  
Yunliang Chen ◽  
David J. Abraham ◽  
Xu Shi-wen ◽  
Jeremy D. Pearson ◽  
Carol M. Black ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Fibroblast Adhesion

In vivo, CCN2 (connective tissue growth factor) promotes angiogenesis, osteogenesis, tissue repair, and fibrosis, through largely unknown mechanisms. In vitro, CCN2 promotes cell adhesion in a variety of systems via integrins and heparin sulfate proteoglycans (HSPGs). However, the physiological relevance of CCN2-mediated cell adhesion is unknown. Here, we find that HSPGs and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascade are required for adult human dermal fibroblasts to adhere to CCN2. Endogenous CCN2 directly binds fibronectin and the fibronectin receptors integrins α4 β1 and α5 and syndecan 4. Using Ccn2-/- mouse embryonic fibroblasts, we show that loss of endogenous CCN2 results in impaired spreading on fibronectin, delayed α-smooth muscle actin stress fiber formation, and reduced ERK and focal adhesion kinase phosphorylation. These results suggest that a physiological role of CCN2 is to potentiate the ability of fibroblasts to spread on fibronectin, which may be important in modulating fibroblast adhesion to the provisional matrix during tissue development and wound healing. These results are consistent with the notion that a principal function of CCN2 is to modulate receptor/ligand interactions in vivo.

Only a specific subset of human peripheral-blood monocytes has endothelial-like functional capacity

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2347-2355 ◽  
Author(s):  
Elzafir Elsheikh ◽  
Mehmet Uzunel ◽  
Zhong He ◽  
Jan Holgersson ◽  
Grzegorz Nowak ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Functional Capacity ◽  
Peripheral Blood ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Endothelial Growth Factor

Abstract The monocyte population in blood is considered a possible source of endothelial precursors. Because endothelial-specific receptor tyrosine kinases act as regulators of endothelial cell function, we investigated whether expression of the vascular endothelial growth factor receptor-2 (VEGFR-2) on monocytes is important for their endothelial-like functional capacity. Peripheral-blood monocytes expressing vascular endothelial growth factor receptor-2 (VEGFR-2), or CD14+/VEGFR-2+, were isolated, and their phenotypic, morphologic, and functional capacities were compared with those of monocytes negative for this marker (CD14+/VEGFR-2-). CD14+/VEGFR-2+ cells constituted approximately 2% ± 0.5% of the total population of monocytes and 0.08% ± 0.04% of mononuclear cells in blood. CD14+/VEGFR-2+ cells exhibited the potential to differentiate in vitro into cells with endothelial characteristics. The cells were efficiently transduced by a lentiviral vector driving expression of the green fluorescence protein (GFP). Transplantation of GFP-transduced cells into balloon-injured femoral arteries of nude mice significantly contributed to efficient reendothelialization. CD14+/VEGFR-2- did not exhibit any of these characteristics. These data demonstrate that the expression of VEGFR-2 on peripheral blood monocytes is essential for their endothelial-like functional capacity and support the notion of a common precursor for monocytic and endothelial cell lineage. Our results help clarify which subpopulations may restore damaged endothelium and may participate in the maintenance of vascular homeostasis.

scholarly journals Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate

1996 ◽  
Vol 5 (5) ◽  
pp. 362-369
Author(s):  
W. A. T. Slieker ◽  
P. Th. W. van Hal ◽  
J. M. Wijkhuijs ◽  
J. P. M. Hopstaken-Broos ◽  
J. A. Noordhoek ◽  
...  
Keyword(s):  
Cell Surface ◽  
Allergic Asthma ◽  
Peripheral Blood ◽  
Beclomethasone Dipropionate ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Hla Dr ◽  
Long Term Treatment ◽  
Inhaled Glucocorticoids

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a β2-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n= 4) or an anticholinergic or placebo (n= 8). We compared the results with healthy volunteers (n= 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p< 0.04) and higher expression of CD13, CD14 and CD18 Ag (p< 0.05,p< 0.02 andp< 0.04, respectively) when compared with the healthy control subjects (n= 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p< 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics.

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

2002 ◽  
Vol 22 (24) ◽  
pp. 8709-8720 ◽  
Author(s):  
Fan-E Mo ◽  
Andrew G. Muntean ◽  
Chih-Chiun Chen ◽  
Donna B. Stolz ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Diseases ◽  
Tissue Growth ◽  
Early Gene ◽  
Matricellular Proteins ◽  
Placental Development ◽  
Ccn Family ◽  
Aberrant Expression ◽  
Vascular Integrity ◽  
Vascular Insufficiency

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 matrix-associated 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: ∼30% 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.

Hepatocyte growth factor–stimulated invasiveness of monocytes

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3964-3969 ◽  
Author(s):  
Mario Beilmann ◽  
George F. Vande Woude ◽  
Hans-Peter Dienes ◽  
Peter Schirmacher
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Peripheral Blood ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Hepatocyte Growth ◽  
Stimulation Of

Abstract Hepatocyte growth factor (HGF) is a pluripotent cytokine with mitogenic, motogenic, and morphogenic activity for mainly epithelial and endothelial target cells. We previously demonstrated that the specific HGF receptor, MET, is induced in stimulated peripheral blood monocytes. In this study, we analyzed the functional consequences of MET activation in primary cultures of peripheral blood monocytes from healthy donors. After stimulation of MET-expressing monocytes with recombinant HGF, the gene-expression profile of peripheral blood mononuclear cells and monocytes was significantly modulated, especially with regard to genes involved in cell movement. After stimulation of primary cultured monocytes with HGF, invasion assays showed a significantly increased matrigel invasion rate that was completely abolished by neutralizing antibodies to HGF. The HGF-activated invasiveness and the altered gene-expression profile suggest a proinflammatory role for HGF stimulation of monocytes and support the hypothesis that the HGF/MET signaling system plays an important part in the activation of the nonspecific cellular inflammatory response.

Increased Transforming Growth Factor-β Production and Gene Expression by Peripheral Blood Monocytes of Hypertensive Patients

Hypertension ◽  
1997 ◽  
Vol 30 (1) ◽  
pp. 134-139 ◽  
Author(s):  
Ettore Porreca ◽  
Concetta Di Febbo ◽  
Gabriella Mincione ◽  
Marcella Reale ◽  
Giovanna Baccante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Peripheral Blood ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Hypertensive Patients

scholarly journals Fisp12/Mouse Connective Tissue Growth Factor Mediates Endothelial Cell Adhesion and Migration through Integrin αvβ3, Promotes Endothelial Cell Survival, and Induces Angiogenesis In Vivo

1999 ◽  
Vol 19 (4) ◽  
pp. 2958-2966 ◽  
Author(s):  
Alexander M. Babic ◽  
Chih-Chiun Chen ◽  
Lester F. Lau
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Connective Tissue ◽  
Tissue Growth ◽  
Microvascular Endothelial Cells ◽  
Endothelial Cell Survival ◽  
Vessel Growth

ABSTRACT Fisp12 was first identified as a secreted protein encoded by a growth factor-inducible immediate-early gene in mouse fibroblasts, whereas its human ortholog, CTGF (connective tissue growth factor), was identified as a mitogenic activity in conditioned media of human umbilical vein endothelial cells. Fisp12/CTGF is a member of a family of secreted proteins that includes CYR61, Nov, Elm-1, Cop-1/WISP-2, and WISP-3. Fisp12/CTGF has been shown to promote cell adhesion and mitogenesis in both fibroblasts and endothelial cells and to stimulate cell migration in fibroblasts. These findings, together with the localization of Fisp12/CTGF in angiogenic tissues, as well as in atherosclerotic plaques, suggest a possible role for Fisp12/CTGF in the regulation of vessel growth during development, wound healing, and vascular disease. In this study, we show that purified Fisp12 (mCTGF) protein promotes the adhesion of microvascular endothelial cells through the integrin receptor αvβ3. Furthermore, Fisp12 stimulates the migration of microvascular endothelial cells in culture, also through an integrin-αvβ3-dependent mechanism. In addition, the presence of Fisp12 promotes endothelial cell survival when cells are plated on laminin and deprived of growth factors, a condition that otherwise induces apoptosis. In vivo, Fisp12 induces neovascularization in rat corneal micropocket implants. These results demonstrate that Fisp12 is a novel angiogenic inducer and suggest a direct role for Fisp12 in the adhesion, migration, and survival of endothelial cells during blood vessel growth. Taken together with the recent finding that the related protein CYR61 also induces angiogenesis, we suggest that Fisp12/mCTGF and CYR61 comprise prototypes of a new family of angiogenic regulators that function, at least in part, through integrin-αvβ3-dependent pathways.

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