Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice

Bergmann, Caroline; Hoefer, Imo E.; Meder, Benjamin; Roth, H; Royen, Niels van; Breit, S.; Jost, Marco; Aharinejad, Seyedhossein; Hartmann, Susanne; Buschmann, Ivo

doi:10.1189/jlb.0206087

Cited by 162 publications

(140 citation statements)

References 47 publications

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“…This finding has been confirmed by recent studies, which demonstrate that monocyte recruitment is central to postnatal blood vessel formation [92][93][94]. This mechanism has, in part, been attributed to the critical role of VEGF in adult neovascularization, and prevention of neovessel regression [95][96][97].…”

Section: Decellularized Tissue-derived Matrices: the Biologic Countersupporting

confidence: 74%

Tissue engineering on matrix: future of autologous tissue replacement

et al. 2011

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Section: Decellularized Tissue-derived Matrices: the Biologic Countersupporting

confidence: 74%

Tissue engineering on matrix: future of autologous tissue replacement

et al. 2011

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“…S8). These findings suggest that the IL-34 gene is a unique target of 1α,25(OH) 2 (28)(29)(30)(31). At the amino acid sequence level, IL-34 gene is more conserved than the CSF-1 gene during evolution (32).…”

Section: Discussionmentioning

confidence: 75%

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

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

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Osteoclasts are generated from monocyte/macrophage-lineage precursors in response to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-κB ligand (RANKL). CSF-1-mutated CSF-1 op/op mice as well as RANKL −/− mice exhibit osteopetrosis (OP) caused by osteoclast deficiency. We previously identified RANKL receptor (RANK)/CSF-1 receptor (CSF-1R) double-positive cells as osteoclast precursors (OCPs), which existed in bone in RANKL −/− mice. Here we show that OCPs do not exist in bone but in spleen in CSF-1 op/op mice, and spleen acts as their reservoir. IL-34, a newly discovered CSF-1R ligand, was highly expressed in vascular endothelial cells in spleen in CSF-1 op/op mice. Vascular endothelial cells in bone also expressed IL-34, but its expression level was much lower than in spleen, suggesting a role of IL-34 in the splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1-induced osteoclastogenesis in CSF-1 op/op mice. Osteoclasts appeared in aged CSF-1 op/op mice with up-regulation of IL-34 expression in spleen and bone. Splenectomy blocked the age-associated appearance of osteoclasts. The injection of 2-methylene-19-nor-(20S)-1α,25(OH) 2 D 3 (2MD), a potent analog of 1α,25-dihidroxyvitamin D 3 , into CSF-1 op/op mice induced both hypercalcemia and osteoclastogenesis. Administration of 2MD enhanced IL-34 expression not only in spleen but also in bone through a vitamin D receptor-mediated mechanism. Either splenectomy or siRNA-mediated knockdown of IL-34 suppressed 2MD-induced osteoclastogenesis. These results suggest that IL-34 plays a pivotal role in maintaining the splenic reservoir of OCPs, which are transferred to bone in response to diverse stimuli, in CSF-1 op/op mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D. CSF-1 is the most potent growth factor for monocytes/macrophages (3), but its synthesis by osteoblasts occurs independently of PTH and 1α,25(OH) 2 D 3 (2). CSF-1 op/op mice cannot produce a functionally active CSF-1 (4), and therefore, exhibit monocytopenia and osteopetrosis (OP) (5, 6). However, several curious phenomena have been observed in CSF-1 op/op mice. First, osteoclasts are totally absent in young CSF-1 op/op mice, but appear in aged CSF-1 op/op mice (7). Second, osteopetrotic characteristics of CSF-1R −/− mice are more severe than those of CSF-1 op/op mice (8). Third, F4/80 + [F4/80(+)] macrophages exist in the splenic red pulp in CSF-1 op/op mice as well as in WT mice, and their number is regulated by a mechanism independently of CSF-1 (9, 10). Fourth, the administration of vascular endothelial growth factor (VEGF) rescues osteopetrosis in CSF-1 op/op mice (11, 12), but VEGF cannot substitute for CSF-1 to induce osteoclast formation in vitro (13).Recently, Lin et al. (14) discovered IL-34, as a new ligand for CSF-1R. The amino acid sequence of IL-34 was quite different from that of CSF-1, but IL-34 promoted macrophage colony formation like CSF-1 did. IL-34 was specifically expressed in splen...

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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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Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice

Cited by 162 publications

References 47 publications

Tissue engineering on matrix: future of autologous tissue replacement

Tissue engineering on matrix: future of autologous tissue replacement

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

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

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