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Brahim Chaqour - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE The Matricellular Protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling
2016Co-Authors: Hemabindu Chintala, Izabela Krupska, Lulu Yan, Lester Lau, Maria Grant, Brahim ChaqourAbstract:Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding Matricellular Protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in themouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing Protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF-R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These datahighlight novel functionsofCCN1asanaturallyoptimizedmolecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses
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the Matricellular Protein ccn1 controls retinal angiogenesis by targeting vegf src homology 2 domain phosphatase 1 and notch signaling
Development, 2015Co-Authors: Hemabindu Chintala, Lester F Lau, Izabela Krupska, Lulu Yan, Maria B Grant, Brahim ChaqourAbstract:Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding Matricellular Protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in the mouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing Protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF-R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These data highlight novel functions of CCN1 as a naturally optimized molecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses.
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the Matricellular Protein cysteine rich Protein 61 ccn1 cyr61 enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy
Journal of Biological Chemistry, 2011Co-Authors: Adeel Hasan, Hemabindu Chintala, Maria B Grant, Nataliya Pokeza, Lynn C Shaw, Hyun Seung Lee, Douglas R Lazzaro, Daniel M Rosenbaum, Brahim ChaqourAbstract:Retinal vascular damages are the cardinal hallmarks of retinopathy of prematurity (ROP), a leading cause of vision impairment and blindness in childhood. Both angiogenesis and vasculogenesis are disrupted in the hyperoxia-induced vaso-obliteration phase, and recapitulated, although aberrantly, in the subsequent ischemia-induced neovessel formation phase of ROP. Yet, whereas the histopathological features of ROP are well characterized, many key modulators with a therapeutic potential remain unknown. The CCN1 Protein also known as cysteine-rich Protein 61 (Cyr61) is a dynamically expressed, Matricellular Protein required for proper angiogenesis and vasculogenesis during development. The expression of CCN1 becomes abnormally reduced during the hyperoxic and ischemic phases of ROP modeled in the mouse eye with oxygen-induced retinopathy (OIR). Lentivirus-mediated re-expression of CCN1 enhanced physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological angiogenesis following ischemia. Remarkably, injection into the vitreous of OIR mice of hematopoietic stem cells (HSCs) engineered to express CCN1 harnessed ischemia-induced neovessel outgrowth without adversely affecting the physiological adaptation of retinal vessels to hyperoxia. In vitro exposure of HSCs to recombinant CCN1 induced integrin-dependent cell adhesion, migration, and expression of specific endothelial cell markers as well as many components of the Wnt signaling pathway including Wnt ligands, their receptors, inhibitors, and downstream targets. CCN1-induced Wnt signaling mediated, at least in part, adhesion and endothelial differentiation of cultured HSCs, and inhibition of Wnt signaling interfered with normalization of the retinal vasculature induced by CCN1-primed HSCs in OIR mice. These newly identified functions of CCN1 suggest its possible therapeutic utility in ischemic retinopathy.
Lester F Lau - One of the best experts on this subject based on the ideXlab platform.
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the Matricellular Protein ccn1 controls retinal angiogenesis by targeting vegf src homology 2 domain phosphatase 1 and notch signaling
Development, 2015Co-Authors: Hemabindu Chintala, Lester F Lau, Izabela Krupska, Lulu Yan, Maria B Grant, Brahim ChaqourAbstract:Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding Matricellular Protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in the mouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing Protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF-R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These data highlight novel functions of CCN1 as a naturally optimized molecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses.
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Matricellular Protein ccn1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts
Molecular and Cellular Biology, 2013Co-Authors: Kihyun Kim, Chih Chiun Chen, Ricardo I Monzon, Lester F LauAbstract:Liver fibrosis occurs as a wound-healing response to chronic hepatic injuries irrespective of the underlying etiology and may progress to life-threatening cirrhosis. Here we show that CCN1, a Matricellular Protein of the CCN (CYR61/CTGF/NOV) family, is accumulated in hepatocytes of human cirrhotic livers. CCN1 is not required for liver development or regeneration, since these processes are normal in mice with hepatocyte-specific Ccn1 deletion. However, Ccn1 expression is upregulated upon liver injuries and functions to inhibit liver fibrogenesis induced by either carbon tetrachloride intoxication or bile duct ligation and promote fibrosis regression. CCN1 acts by triggering cellular senescence in activated hepatic stellate cells and portal fibroblasts by engaging integrin α6β1 to induce reactive oxygen species accumulation through the RAC1-NADPH oxidase 1 enzyme complex, whereupon the senescent cells express an antifibrosis genetic program. Mice with hepatocyte-specific Ccn1 deletion suffer exacerbated fibrosis with a concomitant deficit in cellular senescence, whereas overexpression of hepatic Ccn1 reduces liver fibrosis with enhanced senescence. Furthermore, tail vein delivery of purified CCN1 Protein accelerates fibrosis regression in mice with established fibrosis. These findings reveal a novel integrin-dependent mechanism of fibrosis resolution in chronic liver injury and identify the CCN1 signaling pathway as a potential target for therapeutic intervention.
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ccn1 cyr61 the very model of a modern Matricellular Protein
Cellular and Molecular Life Sciences, 2011Co-Authors: Lester F LauAbstract:CCN1 (CYR61) is a dynamically expressed, multifunctional Matricellular Protein that plays essential roles in cardiovascular development during embryogenesis, and regulates inflammation, wound healing and fibrogenesis in the adult. Aberrant CCN1 expression is associated with myriad pathologies, including various cancers and diseases associated with chronic inflammation. CCN1 promotes diverse and sometimes opposing cellular responses, which can be ascribed, as least in part, to disparate activities mediated through its direct binding to distinct integrins in different cell types and contexts. Accordingly, CCN1 promotes cell proliferation, survival and angiogenesis by binding to integrin αvβ3, and induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans. The ability of CCN1 to trigger the accumulation of a robust and sustained level of reactive oxygen species underlies some of its unique activities as a matrix cell-adhesion molecule. Emerging studies suggest that CCN1 might be useful as a biomarker or therapeutic target in certain diseases.
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the Matricellular Protein ccn1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing
Nature Cell Biology, 2010Co-Authors: Joon Il Jun, Lester F LauAbstract:Cellular senescence is a recognized mechanism of tumour suppression; however, its contribution to other pathologies is not well understood. We show that the Matricellular Protein CCN1 (also known as CYR61; cysteine-rich Protein 61), which is dynamically expressed at sites of wound repair, can induce fibroblast senescence by binding to integrin alpha(6)beta(1) and the heparan sulphate proteoglycans (receptors involved in cell adhesion). CCN1 induces DNA damage response pathways and activates p53 and the RAC1-NOX1 complex, which generates reactive oxygen species (ROS). This results in the ROS-dependent activation of the p16(INK4a)/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes. Senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes in wild-type mice. These processes are lost in knockin mice that express a senescence-defective Ccn1 mutant, resulting in exacerbated fibrosis. Topical application of CCN1 Protein to wounds reverses these defects. Thus, fibroblast senescence is a CCN1-dependent wound healing response in cutaneous injury that functions to curb fibrosis during tissue repair.
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Matricellular Protein ccn1 activates a proinflammatory genetic program in murine macrophages
Journal of Immunology, 2010Co-Authors: Tao Bai, Chih Chiun Chen, Lester F LauAbstract:CCN1 (CYR61) is a Matricellular Protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NF-kappaB activity and enhancing the apoptotic activity of Fas ligand and TRAIL. In this paper, we show that CCN1 supports the adhesion of macrophages through integrin alpha(M)beta(2) and syndecan-4, activates NFkappaB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-alpha, IL-1alpha, IL-1beta, IL-6, and IL-12b), chemokines (MIP-1alpha; MCP-3; growth-related oncogenes 1 and 2; and inflammatory Protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rbeta) and anti-inflammatory factors (TGF-beta1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-kappaB by CCN1, leading to the synthesis of cytokines including TNF-alpha and inflammatory Protein 10; and a delayed response resulting from CCN1-induced TNF-alpha, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1beta and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.
Curzio Ruegg - One of the best experts on this subject based on the ideXlab platform.
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the Matricellular Protein cyr61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis
Oncotarget, 2017Co-Authors: Yuting Huang, Qiang Lan, Girieca Lorusso, Nathalie Duffey, Curzio RueggAbstract:// Yu-Ting Huang 1, 2, * , Qiang Lan 1, 2, * , Girieca Lorusso 1, 2 , Nathalie Duffey 1 , Curzio Ruegg 1, 2 1 Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland 2 National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland * These authors contributed equally to this work Correspondence to: Curzio Ruegg, email: curzio.ruegg@unifr.ch Keywords: CYR61, metastasis, extravasation, anoikis resistance Received: June 20, 2016 Accepted: November 19, 2016 Published: November 29, 2016 ABSTRACT Matricellular Proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the Matricellular Protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β 1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β 1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung.
Helene E Sage - One of the best experts on this subject based on the ideXlab platform.
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processing of the Matricellular Protein hevin in mouse brain is dependent on adamts4
Journal of Biological Chemistry, 2010Co-Authors: Matthew S Weaver, Helene E Sage, Gail Workman, Marina Cardovila, Wadih Arap, Renata PasqualiniAbstract:The Matricellular SPARC family member hevin (SPARC-like 1/SPARCL-1/SC1/Mast9) contributes to neural development and alters tumor progression in a range of mammalian models. The distribution of hevin in mouse tissues was reexamined with a novel monoclonal antibody that discriminates between hevin and its ortholog SPARC. We now report proteolysis of hevin in many tissues, with the most extensive processing in the brain. We demonstrate a cleavage site within the hevin sequence for the neural tissue Proteinase ADAMTS4. Digestion of hevin by ADAMTS4 in vitro produced fragments similar to those present in brain lysates. Monoclonal antibodies revealed a SPARC-like fragment generated from hevin that was co-localized with ADAMTS4 in vivo. We show that proteolysis of hevin by ADAMTS4 in the mouse cerebellum is important for the normal development of this tissue. In conclusion, we have identified the fragmentation of hevin by ADAMTS4 in the mouse brain and propose that this specific proteolysis is integral to cell morphology and extracellular matrix deposition in the developing brain.
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disruption of the thrombospondin 2 gene alters the lamellar morphology but does not permit vascularization of the adult mouse lumbar disc
Arthritis Research & Therapy, 2008Co-Authors: Helen E Gruber, Paul Bornstein, Helene E Sage, Jane A Ingram, Natalia Zinchenko, James H Norton, Edward N HanleyAbstract:Introduction The biological basis for the avascular state of the intervertebral disc is not well understood. Previous work has suggested that the presence of thrombospondin-1 (TSP-1), a Matricellular Protein, in the outer annulus reflects a role for this Protein in conferring an avascular status to the disc. In the present study we have examined thrombospondin-2 (TSP-2), a Matricellular Protein with recognized anti-angiogenic activity in vivo and in vitro.
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Matricellular Protein sparc is translocated to the nuclei of immortalized murine lens epithelial cells
Journal of Cellular Physiology, 2005Co-Authors: Helene E Sage, Q Yan, Matt Weaver, Nikole PerdueAbstract:The Matricellular glycoProtein, secreted Protein acidic and rich in cysteine (SPARC), has complex biological activities and is important for lens epithelial cell function and regulation of cataract formation. To understand how SPARC influences lens epithelial cell activity and homeostasis, we have studied the subcellular distribution of SPARC in murine lens epithelial cells in vitro. We demonstrate that endogenous SPARC is located in the cytoplasm of either quiescent or dividing lens epithelial cells in culture. However, cytoplasmic SPARC was translocated into the nuclei of immortalized lens epithelial cells upon a significant reduction of intracellular SPARC in these cells. Recombinant human (rh) SPARC added to the culture media was quickly and efficiently internalized into the cytosol of SPARC-null lens epithelial cells. Moreover, cytoplasmic rhSPARC was also translocated into the nucleus after exogenous rhSPARC was removed from the culture media. The translocation of SPARC into the nucleus was therefore triggered by the reduction of SPARC Protein normally available to the cells. A mouse SPARC-EGFP chimeric fusion Protein (70 kDa) was expressed in lens epithelial cells and 293-EBNA cells, and was observed both in the cytoplasm and culture medium, but not in the nucleus. SPARC does not appear to have a strong nuclear localization sequence. Alternatively, SPARC might pass through the nuclear pore complex by passive diffusion. SPARC therefore functions not only as an extracellular Protein but also potentially as an intracellular Protein to influence cellular activities and homeostasis.
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expression of the Matricellular Protein sparc in murine lens sparc is necessary for the structural integrity of the capsular basement membrane
Journal of Histochemistry and Cytochemistry, 2003Co-Authors: Q Yan, David J Blake, John I Clark, Helene E SageAbstract:SUMMARY SPARC (Secreted Protein, Acidic and Rich in Cysteine) is a Matricellular glycoProtein that modulates cell proliferation, adhesion, migration, and extracellular matrix (ECM) production. Although SPARC is generally abundant in embryonic tissues and is diminished in adults, we have found that the expression of SPARC in murine lens persists throughout embryogenesis and adulthood. Our previous studies showed that targeted ablation of the SPARC gene in mice results in cataract formation, a pathology attributed partially to an abnormal lens capsule. Here we provide evidence that SPARC is not a structural component of the lens capsule. In contrast, SPARC is abundant in lens epithelial cells, and newly differentiated fiber cells, with stable expression in wild-type mice up to 2 years of age. Pertubation of the lens capsule in animals lacking SPARC appears to be a consequence of the invasion of the lens cells situated beneath the capsule. Immunoreactivity for SPARC in the lens cells was uneven, with minimal reactivity in the epithelial cells immediately anterior to the equator. These epithelial cells appeared essentially noninvasive in SPARC-null mice, in comparison to the centrally located anterior epithelial cells, in which strong labeling by anti-SPARC IgG was observed. The posterior lens fibers exhibited cytoplasmic extensions into the posterior lens capsule, which was severely damaged in SPARC-null lenses. The expression of SPARC in wild-type lens cells, together with the abnormal lens capsule in SPARC-null mice, indicated that the structural integrity of the lens capsule is dependent on the Matricellular Protein SPARC. The effects of SPARC in the lens appear to involve regulation of lens epithelial and fiber cell morphology and functions rather than deposition as a structural component of the lens capsule. (J Histochem Cytochem 51:503‐511, 2003)
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sparc a Matricellular Protein that functions in cellular differentiation and tissue response to injury
Journal of Clinical Investigation, 2001Co-Authors: Amy D Bradshaw, Helene E SageAbstract:Expressed during many stages of development in a variety of organisms, the Matricellular Protein SPARC (secreted Protein acidic and rich in cysteine, also known as osteonectin or BM-40) is restricted in adult vertebrates primarily to tissues that undergo consistent turnover or to sites of injury and disease (1). The capacity of SPARC to bind to several resident Proteins of the ECM, to modulate growth factor efficacy, to affect the expression of matrix metalloProteinases, and to alter cell shape as a counteradhesive factor, supports the idea that SPARC acts to regulate cell interaction with the extracellular milieu during development and in response to injury (Figure (Figure1;1; see also ref. 1). SPARC is a member of a gene family whose members share structural similarities in one or more Protein domains (1). In addition to the numerous studies in cultured cells, the function of SPARC in vivo has been examined primarily in three evolutionarily diverse organisms — Caenorhabditis elegans, Xenopus laevis, and mice. These systems have been used to study the effects of increased or inappropriate SPARC expression, as well as diminished activity resulting from the inactivation of SPARC mRNA, the blocking of Protein activity, or mutation of the SPARC gene (Table (Table1).1). This Perspective will integrate results from studies in vitro with findings in vivo in an attempt to clarify the current information and to propose functions for SPARC in living tissues.
Hemabindu Chintala - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE The Matricellular Protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling
2016Co-Authors: Hemabindu Chintala, Izabela Krupska, Lulu Yan, Lester Lau, Maria Grant, Brahim ChaqourAbstract:Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding Matricellular Protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in themouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing Protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF-R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These datahighlight novel functionsofCCN1asanaturallyoptimizedmolecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses
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the Matricellular Protein ccn1 controls retinal angiogenesis by targeting vegf src homology 2 domain phosphatase 1 and notch signaling
Development, 2015Co-Authors: Hemabindu Chintala, Lester F Lau, Izabela Krupska, Lulu Yan, Maria B Grant, Brahim ChaqourAbstract:Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding Matricellular Protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in the mouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing Protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF-R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These data highlight novel functions of CCN1 as a naturally optimized molecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses.
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the Matricellular Protein cysteine rich Protein 61 ccn1 cyr61 enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy
Journal of Biological Chemistry, 2011Co-Authors: Adeel Hasan, Hemabindu Chintala, Maria B Grant, Nataliya Pokeza, Lynn C Shaw, Hyun Seung Lee, Douglas R Lazzaro, Daniel M Rosenbaum, Brahim ChaqourAbstract:Retinal vascular damages are the cardinal hallmarks of retinopathy of prematurity (ROP), a leading cause of vision impairment and blindness in childhood. Both angiogenesis and vasculogenesis are disrupted in the hyperoxia-induced vaso-obliteration phase, and recapitulated, although aberrantly, in the subsequent ischemia-induced neovessel formation phase of ROP. Yet, whereas the histopathological features of ROP are well characterized, many key modulators with a therapeutic potential remain unknown. The CCN1 Protein also known as cysteine-rich Protein 61 (Cyr61) is a dynamically expressed, Matricellular Protein required for proper angiogenesis and vasculogenesis during development. The expression of CCN1 becomes abnormally reduced during the hyperoxic and ischemic phases of ROP modeled in the mouse eye with oxygen-induced retinopathy (OIR). Lentivirus-mediated re-expression of CCN1 enhanced physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological angiogenesis following ischemia. Remarkably, injection into the vitreous of OIR mice of hematopoietic stem cells (HSCs) engineered to express CCN1 harnessed ischemia-induced neovessel outgrowth without adversely affecting the physiological adaptation of retinal vessels to hyperoxia. In vitro exposure of HSCs to recombinant CCN1 induced integrin-dependent cell adhesion, migration, and expression of specific endothelial cell markers as well as many components of the Wnt signaling pathway including Wnt ligands, their receptors, inhibitors, and downstream targets. CCN1-induced Wnt signaling mediated, at least in part, adhesion and endothelial differentiation of cultured HSCs, and inhibition of Wnt signaling interfered with normalization of the retinal vasculature induced by CCN1-primed HSCs in OIR mice. These newly identified functions of CCN1 suggest its possible therapeutic utility in ischemic retinopathy.