Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb.

Arras, Margarete; Ito, Wulf; Scholz, Dimitri; Winkler, Bernd; Schaper, Jutta; Schäper, Wolfgang

doi:10.1172/jci119877

Cited by 695 publications

(571 citation statements)

References 32 publications

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“…Here, DNMT1 inhibition increased arteriogenic capacity by ≈44% in nonreversed segments, while there was no effect on reversed flow segments ( P =0.163), indicating that this response is not limited to the C57BL/6 strain. We also sought to determine whether this increased arteriogenic capacity in nonreversed flow segments following DNMT1 inhibition corresponded to altered macrophage recruitment, a necessary component of collateral artery growth45, 46, 47, 48, 49, 50, 52 in vivo. Nonreversed flow collateral segments exhibited a trend ( P =0.057) toward increased pericollateral Mac3 + macrophages in 5AZA‐treated mice (day 17 post FAL, 3 days of 5AZA treatment), corresponding to our previous in vitro results (Figure S7).…”

Section: Resultsmentioning

confidence: 99%

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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BackgroundArteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original “set point.” However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)–dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.Methods and ResultsIn femoral artery ligation–operated C57BL/6 mice, collateral artery segments exposed to increased shear stress without a change in flow direction (ie, nonreversed flow) exhibited global DNA hypermethylation (increased 5‐methylcytosine staining intensity) and constrained arteriogenesis (30% less diameter growth) when compared with segments exposed to both an increase in shear stress and reversed‐flow direction. In vitro, ECs exposed to a flow waveform biomimetic of nonreversed collateral segments in vivo exhibited a 40% increase in DNMT1 expression, genome‐wide hypermethylation of gene promoters, and a DNMT1‐dependent 60% reduction in proarteriogenic monocyte adhesion compared with ECs exposed to a biomimetic reversed‐flow waveform. These results led us to test whether DNMT1 regulates arteriogenic capacity in vivo. In femoral artery ligation–operated mice, DNMT1 inhibition rescued arteriogenic capacity and returned shear stress back to its original set point in nonreversed collateral segments.ConclusionsIncreased shear stress without a change in flow direction initiates arteriogenic growth; however, it also elicits DNMT1‐dependent EC DNA hypermethylation. In turn, this diminishes mechanosensing, augments shear stress set point, and constrains the ultimate arteriogenic capacity of the vessel. This epigenetic effect could impact both endogenous collateralization and treatment of arterial occlusive diseases.

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Section: Resultsmentioning

confidence: 99%

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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“…3 Tumor necrosis factor-␣ (TNF-␣), a macrophage/monocyte-derived pluripotent mediator, can function as both a proangiogenic and antiangiogenic factor. 4 -6 These divergent TNF-␣ effects have been attributed to TNF-␣ concentration and duration of the exposure.…”

Section: Clinical Perspective P 762mentioning

confidence: 99%

Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

Qin²,

et al. 2007

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Background-Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-␣ (TNF-␣), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-␣ receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. Methods and Results-We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. Conclusions-Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases. (Circulation. 2007;115:752-762.)

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“…In malignant disease, the process of macrophage activation was connected with an antitumour activity (Lavnikova et al, 1996;Ragnhammar, 1996) and stimulation of angiogenesis (Polverini and Leibovich, 1984;Arras et al, 1998), the latter being mediated through the secretion of extracellular matrix degrading enzymes and several angiogenic cytokines, including the TP/PD-ECGF (Sunderkotter et al, 1994;Leek et al, 2000). Tumour associated macrophages (TAMs) express TP, but recruitment of activated macrophages into the tumour by tumour cells expressing TP may also contribute to angiogenesis.…”

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confidence: 99%

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

et al. 2002

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Thymidine phosphorylase is an angiogenic factor primarily expressed by cancer cells, stromal cells and tumour-associated macrophages in many human malignancies. These different types of thymidine phosphorylase-expressing cells, however, may have a distinct place in the angiogenic process, and this question was addressed in the present study. A series of 20 normal/ hyperplastic prostate glands and 60 prostate carcinomas was investigated by immunohistochemistry, using specific antibodies for thymidine phosphorylase (P-GF.44C), tumour-associated macrophages (CD68), endothelium (CD31) and prostate specific antigen (ER-PR8). Thymidine phosphorylase expression by normal and hyperplastic epithelial or stromal cells occurred almost exclusively in the context of an intense lymphocytic infiltrate. High thymidine phosphorylase cancer cells and thymidine phosphorylase stromal cells expression was associated with high angiogenesis in prostate carcinomas, and this significant association was extended to include both tumour-associated macrophages and tumour-infiltrating lymphocytes. Thymidine phosphorylase expression and tumour-infiltrating lymphocytes were related inversely with prostate specific antigen reactivity. In conclusion, thymidine phosphorylase is a major angiogenic factor in prostate carcinomas and its up-regulation is likely to occur in the context of a host immune response.

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Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb.

Cited by 695 publications

References 32 publications

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

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