Crucial Role of Stromal Cell–Derived Factor-1α in Neointima Formation After Vascular Injury in Apolipoprotein E–Deficient Mice

Schober, Andreas; Knarren, Sandra; Lietz, Michael; Lin, Elisa A.; Weber, Christian

doi:10.1161/01.cir.0000099508.76665.9a

Cited by 185 publications

(181 citation statements)

References 28 publications

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“…Therefore, induction of SDF-1 expression seems to have a major role in initiating revascularization of the ischemic injured tissues. In support of these findings, SDF-1 is expressed on endothelial cells and pericytes of hypoxic, injured or pathological tissues, including injured carotid arteries and atherosclerotic plaques (Table 1) [22]. Finally, EPCs themselves express and secrete SDF-1 together with VEGF-A [23].…”

Section: Expression Of Sdf-1 In Hypoxic Tissuesmentioning

confidence: 68%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

530

382

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Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4 + BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4 + VEGFR1 + hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.

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Section: Expression Of Sdf-1 In Hypoxic Tissuesmentioning

confidence: 68%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

530

382

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“…Furthermore, high concentrations of SDF-1 gradients generated locally by endothelial cells and fibroblasts present within ischemic injuries serve to attract circulating CXCR4-expressing progenitor cells, notably HPCs, EPCs, and possibly tissue progenitor cells into the injured sites, facilitating repair through the stimulation of angiogenesis and resulting regeneration of epithelial cell compartments. [14][15][16][17] Our findings revealed that the SDF-1-CXCR4 signaling axis is also used to recruit EPCs into tumors, thereby indicating an additional biological resemblance between tumor stroma and the stroma in sites of wound healing.…”

Section: Significant Involvement Of the Sdf-1-cxcr4 Axis In Formationmentioning

confidence: 75%

Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type

Orimo¹,

Weinberg²

2006

Cell Cycle

739

581

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Tumors are highly complex tissues composed of neoplastic cells and, in the case of carcinomas, stromal cell compartments containing a variety of mesenchymal cells, notably fibroblasts, myofibroblasts, endothelial cells, pericytes, and a variety of inflammatory cells associated with the immune system. Fibroblasts and myofibroblasts often represent the majority of the stromal cells within various types of human carcinomas, yet the specific contributions of these cells to tumor growth are poorly understood. Recent work has demonstrated that stromal fibroblast fractions, named carcinoma-associated fibroblasts (CAFs), that have been extracted from a number of invasive human breast carcinomas are more competent to promote the growth of mammary carcinoma cells and to enhance tumor angiogenesis than are comparable cells derived from outside of these tumor masses. CAFs include large populations of myofibroblasts that secrete elevated levels of stromal cell-derived factor 1 (SDF-1), also called CXCL12, which plays a central role in the promotion of tumor growth and angiogenesis; CAF-derived SDF-1 not only stimulates carcinoma cell growth directly through the CXCR4 receptor displayed on tumor cells but also serves to recruit endothelial progenitor cells (EPCs) into tumors, thereby furthering neoangiogenesis. In this review, we highlight the importance of this SDF-1-CXCR4 signaling pathway in the tumor microenvironment and discuss the mechanisms by which stromal fibroblasts within mammary carcinomas enhance tumor growth.

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“…Up-regulation of fbln-5 in the adventitia at day 28 suggests that fbln-5 may be involved in regulation of the adventitial response to vascular injury. Alternatively, loss of fbln-5 may facilitate recruitment of bone marrow-derived progenitor cells to the injured vessel (33).…”

Section: Discussionmentioning

confidence: 99%

Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration

Spencer

Hacker

Davis

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

107

101

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Fibulin (fbln)-5 is an elastin-binding protein required for assembly and organization of elastic fibers. To examine the potential role of fbln-5 in vascular remodeling and neointima formation, we induced vascular injury by carotid artery ligation in fbln-5 ؊/؊ mice. Mutant mice displayed an exaggerated vascular remodeling response that was accompanied by severe neointima formation with thickened adventitia. These abnormalities were not observed in elastin ؉/؊ mice that exhibited a comparable reduction of vessel extensibility to fbln-5 ؊/؊ mice. Thus, the severe remodeling response could not be attributed to altered extensibility of the vessel wall alone. Vascular smooth muscle cells cultured from fbln-5 ؊/؊ mice displayed enhanced proliferative and migratory responses to mitogenic stimulation relative to wild-type cells, and these responses were inhibited by overexpression of fbln-5. These findings demonstrate the importance of the elastic laminae in vascular injury, and reveal an unexpected role of fbln-5 as an inhibitor of vascular smooth muscle cell proliferation and migration.elastic fibers ͉ extracellular matrix ͉ neointima ͉ elastin V ascular obstructive abnormalities, such as atherosclerosis and restenosis after percutaneous coronary intervention, are triggered by damage to the vessel wall, initiating a series of biological responses, including up-regulation of adhesion molecules, recruitment of inflammatory cells, secretion of cytokines, and activation of smooth muscle cells (SMCs). Activated SMCs secrete growth factors, extracellular matrix proteins, and matrix proteases, thereby altering the microenvironment of the injured vessel wall. Much attention has focused on the signaling pathways responsible for the proliferation and migration of SMCs associated with vascular obstruction, but relatively little is known of the potential contributions of extracellular matrix proteins to these processes (reviewed in ref. 1).Structural changes of the vessel wall induced by mechanical force or enzymatic digestion also influence the development of vascular obstructive disease (2, 3). The elastic lamina plays a critical role in maintaining the integrity of the vessel wall. Rupture of the external elastic lamina (EEL) is a more potent stimulus for neointima formation than injury involving the internal elastic lamina (IEL) alone after coronary artery stent-induced injury (4). In addition, exposure of the adventitia to the blood lumen by disruption of the EEL during percutaneous angioplasty increases the activation of adventitial myofibroblasts, leading to adventitial fibrosis that eventually constricts the vessel wall (5).The perception of the elastic lamina (or elastic fibers) as the sole structural component of the vessel wall was recently challenged by the view that elastic fibers actively modulate intercellular signaling. Elastin (eln), a major component of the elastic fibers in the arterial wall, inhibits proliferation of SMCs (6). Eln is secreted as a tropoelastin monomer and subsequently undergoes cross-linking t...

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Crucial Role of Stromal Cell–Derived Factor-1α in Neointima Formation After Vascular Injury in Apolipoprotein E–Deficient Mice

Cited by 185 publications

References 28 publications

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type

Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration

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