Interplay of CCR2 signaling and local shear force determines vein graft neointimal hyperplasia in vivo

Jiang, Zhihua; Yu, Peng; Tao, Ming; Ifantides, Cristos; Ozaki, C. Keith; Berceli, Scott A.

doi:10.1016/j.febslet.2009.10.015

Cited by 13 publications

(21 citation statements)

References 18 publications

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“…35 Preclinical studies proposed the role of macrophages in neointima formation in vein grafts. 16, 36, 37 However, no medical therapies are currently available to target vein graft inflammation, which has driven our current efforts.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development

Koga

Nakano

Dahlman

et al. 2015

ATVB

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Objective Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results We used two biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: 1) blocking antibody; and 2) macrophage- or endothelial cell (EC)-targeted small-interfering RNA (siRNA). Dll4 antibody administration for 28 days inhibited vein graft lesion development in LDL-receptor deficient (Ldlr−/−) mice, and suppressed macrophage accumulation and macrophage expression of pro-inflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at Day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, while EC-targeted Dll4 siRNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces pro-inflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell (SMC) proliferation and migration and suppressed their differentiation. Conclusion These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and SMC, supporting the Dll4-Notch axis as a novel therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development

Koga

Nakano

Dahlman

et al. 2015

ATVB

Self Cite

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“…Recent studies from our laboratory showed that the pericardial patch may be a unique niche microenvironment that attracts endothelial progenitor cells after implantation, promoting incorporation into the host vessel that may be responsible for long term durability and clinical success1819. Although open venous surgery is performed less frequently compared to open arterial surgery, patches are also used in venous surgery20, as venous procedures are frequently complicated by aggressive neointimal hyperplasia and restenosis, possibly due to the lower shear stress in the venous system2122232425. In addition, patients with severe vascular disease may develop spontaneous venous neointimal hyperplasia26, placing them at additional risk after conventional venous interventions.…”

Section: Discussionmentioning

confidence: 99%

Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

Bai

Lee

Chen

et al. 2017

Sci Rep

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Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

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“…Likewise, time and again, hemodynamic stress has been shown in animal models to influence the development of intimal hyperplasia. [18, 19, 181] High shear conditions skew the cytokine repertoire to a Th2 type response with lower inflammatory and higher anti-inflammatory cytokines compared with low shear stress. [182] However, blood flow and shear stress are largely un-modifiable factors dictated by the inflow and outflow conditions and vein diameter.…”

Section: Discussionmentioning

confidence: 99%

Vein graft failure

Owens

Gasper

Rahman

et al. 2015

Journal of Vascular Surgery

119

107

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Following the creation of an autogenous lower extremity bypass graft, the vein must undergo a series of dynamic structural changes to stabilize the arterial hemodynamic forces. These changes, commonly referred to as remodeling, include an inflammatory response, the development of a neointima, matrix turnover, and cellular proliferation and apoptosis. The sum total of these processes results in dramatic alterations in the physical and biomechanical attributes of the arterialized vein. The most clinically obvious and easily measured of these is lumen remodeling of the graft. However, though somewhat less precise, wall thickness, matrix composition, and endothelial changes can be measured in vivo within the healing vein graft. Recent translational work has demonstrated the clinical relevance of remodeling as it relates to vein graft patency and the systemic factors influencing it. By correlating histologic and molecular changes in the vein, insights into potential therapeutic strategies to prevent bypass failure and areas for future investigation are explored.

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Interplay of CCR2 signaling and local shear force determines vein graft neointimal hyperplasia in vivo

Cited by 13 publications

References 18 publications

Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development

Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development

Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

Vein graft failure

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