CCL2 Regulates Angiogenesis via Activation of Ets-1 Transcription Factor

Stamatovic, Svetlana M.; Keep, Richard F.; Mostarica-Stojković, Marija; Andjelkovic, Anuska V.

doi:10.4049/jimmunol.177.4.2651

Cited by 165 publications

(150 citation statements)

References 52 publications

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“…The TFBS for members of the ETS family like ETS-1, ELF-1, and SPI1 which are involved in regulation of extracellular matrix (46), vascular development (47), and cellular migration (48), were also significantly overrepresented during endotoxin tolerance. These findings could also be connected to the substantial upregulation of MCP-1 (CCL-2) observed in our time-course experiments during endotoxin tolerance, as MCP-1 has been previously linked with the regulation of angiogenesis through activation of the ETS-1 transcription factor (49).…”

Section: Discussionmentioning

confidence: 58%

Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells

Pena

Pistolic

Raj

et al. 2011

The Journal of Immunology

216

212

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Classical (M1) and alternative (M2) polarization of mononuclear cells (MNCs) such as monocyte and macrophages is known to occur in response to challenges within a microenvironment, like the encounter of a pathogen. LPS, also known as endotoxin, is a potent inducer of inflammation and M1 polarization. LPS can also generate an effect in MNCs known as endotoxin tolerance, defined as the reduced capacity of a cell to respond to LPS activation after an initial exposure to this stimulus. Using systems biology approaches in PBMCs, monocytes, and monocyte-derived macrophages involving microarrays and advanced bioinformatic analysis, we determined that gene responses during endotoxin tolerance were similar to those found during M2 polarization, featuring gene and protein expression critical for the development of key M2 MNC functions, including reduced production of proinflammatory mediators, expression of genes involved in phagocytosis, as well as tissue remodeling. Moreover, expression of different metallothionein gene isoforms, known for their role in the control of oxidative stress and in immunomodulation, were also found to be consistently upregulated during endotoxin tolerance. These results demonstrate that after an initial inflammatory stimulus, human MNCs undergo an M2 polarization probably to control hyperinflammation and heal the affected tissue.

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Section: Discussionmentioning

confidence: 58%

Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells

Pena

Pistolic

Raj

et al. 2011

The Journal of Immunology

216

212

View full text Add to dashboard Cite

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“…38,39 However, it has been shown that CCL2 may also have a direct effect on angiogenesis. 40,41 Our current findings suggest that CCL2 expression is modulated by TF in ECs. Indeed, we found that endogenous TF can promote microvessel stabilization through CCL2 expression, promoting via HVSMC-CCR2 migration to the newly formed endothelial tubes, which agrees with the finding that CCL2 stimulates SMC migration.…”

Section: Discussionmentioning

confidence: 73%

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Arderiu

Peña

Aledo

et al. 2011

ATVB

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Objective-Tissue factor (TF) triggers arterial thrombosis. TF is also able to initiate cellular signaling mechanisms leading to angiogenesis. Because high cardiovascular risk atherosclerotic plaques show significant angiogenesis, our objective was to investigate whether TF is able to trigger and stabilize atherosclerotic plaque neovessel formation. Methods and Results-In this study, we showed, by real-time confocal microscopy in 3-dimensional basement membrane cocultures, that TF in human microvascular endothelial cells (HMEC-1) and in human vascular smooth muscle cells (HVSMCs) plays an important role in the formation of capillary-like networks. TF silencing in endothelial cells and smooth muscle cells inhibits the formation of tube-like structures with stable phenotype. Using an in vivo model, we observed that TF inhibition in either HMEC-1 or HVSMCs reduced their shared ability to form new capillaries. The phenotypic changes induced by TF silencing were linked to reduced chemokine (C-C motif) ligand 2 (CCL2) expression in endothelial cells. Wound healing and chemotactic assays demonstrated that TF-induced release of CCL2 stimulated HVSMC migration to HMEC-1. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ cytokines Ⅲ endothelial function Ⅲ vascular biology A therosclerotic plaque angiogenesis, the outgrowth of new capillaries from preexisting vascular networks, is a pathological feature of advanced complicated plaques. 1,2 Interestingly, coronary type VI plaques, according to the American Heart Association classification, are those with higher amount of microvessels and those with higher risk of inducing a clinical cardiovascular event. 3 In advanced plaques, inflammatory cell infiltration and concomitant production of proangiogenic cytokines may be responsible for induction of uncontrolled neointimal microvessel proliferation resulting in production of immature and fragile neovessels. The final stage of microvessel formation occurs when maturation requires the formation of tight endothelial cell-tocell contacts, 4 the downregulation of endothelial proliferation, and the deposition of a basal lamina to which the endothelium tightly adheres, as well as the recruitment of supporting cells to the vessel wall, such as pericytes and smooth muscle cells (SMCs). 5,6 During angiogenesis, the communication between endothelial cells (ECs) and SMCs requires a precise temporal and spatial regulation of pro-and antiangiogenic molecules, but the process is not yet fully understood. Conclusion-Endogenous See accompanying article on page 2364In recent years, it has become clear that the angiogenesis process is highly dependent on components of the blood coagulation cascade. One of these proteins is tissue factor (TF). 7-9 TF is the cellular receptor and cofactor for blood coagulation factor VII (FVII). 10,11 In addition to its primary role in blood coagulation, accumulating evidence has transformed our view of TF from the cellular receptor for activated FVII (FVIIa) to a multifaceted transmembrane signaling receptor. The bioch...

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“…In vivo, CCL2-mediated angiogenesis has been demonstrated in corneal implantation, chick chorioallantoic membrane, Matrigel plug, and sponge implantation models (33)(34)(35), and appears to be independent of its induction of leukocyte recruitment (34). The chemotaxis of endothelial cells by CCL2 is dependent on CCL2-induced over-expression of membrane type 1-metalloproteinase on endothelial cell surfaces (31) and is mediated via the ERK cascade and the transcription factor Ets-1 (36).…”

Section: Chemokinesmentioning

confidence: 99%

Chemokines as mediators of angiogenesis

Mehrad¹,

Keane²,

Strieter³

2007

Thromb Haemost

179

145

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SummaryChemokines were originally described as cytokines that mediate leukocyte recruitment to sites of inflammation. Members of a subgroup of chemokines, the CXC family, also play a critical role in both physiologic and pathologic angiogenesis, including in the context of chronic inflammation, fibrosis, and malignancy. A unique feature of this family of cytokines is that, on the basis of their structure and receptor binding, individual ligands display either angiogenic or angiostatic biological activity in the regulation of angiogenesis. In this review, we summarize the key literature in this growing field.

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CCL2 Regulates Angiogenesis via Activation of Ets-1 Transcription Factor

Cited by 165 publications

References 52 publications

Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells

Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Chemokines as mediators of angiogenesis

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