Host-Derived Smooth Muscle Cells Accumulate in Cardiac Allografts: Role of Inflammation and Monocyte Chemoattractant Protein 1

Cao

et al. 2013

Sci Rep

Self Cite

116

The functional impact of amyloid peptides (Aβs) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimer's patients. Here we show substantial accumulation of Aβs 40 and 42 in the brain arterioles of Alzheimer's patients and of transgenic Alzheimer's mice. Purified Aβs 1–40 and 1–42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimer's patients. VEGF significantly prevented Aβ-induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimer's. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimer's disease.

Section: Methodsmentioning

confidence: 99%

“…Paraffin-embedded samples were prepared according to the standard method33. Tissue sections were re-hydrated in xylene-graded ethanol, and immersed in water for 5 min followed by treatment with 0.3% hydrogen peroxide and 70% methanol for 20 min.…”

Section: Methodsmentioning

confidence: 99%

VEGF significantly restores impaired memory behavior in Alzheimer's mice by improvement of vascular survival

Cao

et al. 2013

Sci Rep

Self Cite

116

“…The results suggested that recipient bone marrow cells were the major origin of neointimal smooth muscle cells, and they contributed to the neointimal hyperplasia of aortic allografts. It has been reported that the amount of host-derived SMC proliferation in neointima correlates with the number of infiltrating leukocytes and acute rejection [40]. Stem cells have been found to perform similarly as leukocytes in many ways.…”

Section: Smooth Muscle Cells and Smooth Muscle-like Cellsmentioning

confidence: 99%

Mechanism of arterial remodeling in chronic allograft vasculopathy

2011

Chronic allograft vasculopathy (CAV) remains a major obstacle for long-term survival of grafts even though therapeutic strategies have improved considerably in recent years. CAV is characterized by concentric and diffuse neointimal formation, medial apoptosis, infiltration of lymphocyte or inflammatory cells, and deposition of extracellular matrix both in arteries and veins. Recent studies have shown that stem cells derived from the recipient contribute to neointimal formation under the regulation of chemokines and cytokines. Arterial remodeling in allografts eventually causes ischemic graft failure. The pathogenesis is multi-factorial with both immunologic and non-immunological factors being involved. The immunological factors have been discussed extensively in other articles. This review focuses mainly on the arterial remodeling that occurs in 3 layers of vessel walls including intimal injury, accumulation of smooth muscle-like cells in the neointimal, medial smooth muscle cell apoptosis, adventitial fibrosis, and deposition of extracellular matrix.

“…43 Synthetic SMCs can migrate in response to PFGF-BB, but MCP-1 and RANTES can also stimulate their migration. 16,17,64,65 Thus, chemokines can selectively mediate the local recruitment of distinct leukocytes and other cell types, such as SMCs or vascular progenitor cells that contribute to intimal hyperplasia. 66 Interestingly, c-kit-positive cells contribute to intimal hyperplasia by a process that may also involve SDF-1.…”

Section: Discussionmentioning

confidence: 99%

“…SMC migration can be stimulated by chemotactic growth factors, such as platelet-derived growth factor BB, released from degranulating platelets, and by chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES). [16][17][18] Endothelial damage induces the expression of tissue plasminogen activator and matrix metalloproteinases that facilitate SMC migration to the intima. Other factors, such as vascular endothelial growth factor A, granulocyte colony-stimulating factor, and stromal cell-derived factor 1 (SDF-1), may also be responsible for the recruitment and mobilization of vascular progenitors from the bone marrow.…”

mentioning

confidence: 99%

Monocyte Chemoattractant Protein 1–Mediated Migration of Mesenchymal Stem Cells Is a Source of Intimal Hyperplasia

Grudzińska

Kurzejamska

Bojakowski

et al. 2013

ATVB

Self Cite

Objective-Intimal hyperplasia is considered to be a healing response and is a major cause of vessel narrowing after injury, where migration of vascular progenitor cells contributes to pathological events, including transplant arteriosclerosis. Approach and Results-In this study, we used a rat aortic-allograft model to identify the predominant cell types associated with transplant arteriosclerosis and to identify factors important in their recruitment into the graft. Transplantation of labeled adventitial tissues allowed us to identify the adventitia as a major source of cells migrating to the intima. RNA microarrays revealed a potential role for monocyte chemoattractant protein 1 (MCP-1), stromal cell-derived factor 1, regulated on activation, normal T cell expressed and secreted, and interferon-inducible protein 10 in the induced vasculopathy. MCP-1 induced migration of adventitial fibroblast cells. CCR2, the receptor for MCP-1, was coexpressed with CD90, CD44, NG2, or sca-1 on mesenchymal stem cells. In vivo experiments using MCP-1-deficient and CCR2-deficient mice confirmed an important role of MCP-1 in the formation of intimal hyperplasia in a mouse model of vascular injury. The aim of this study was to examine the contribution of MSCs in intimal hyperplasia and to identify relevant factors that affect their recruitment. We found that local inflammation in transplanted vessels exerts an effect on surrounding tissue and vessels that leads to phenotypic modulation of SMCs; however, those cells did not migrate to the intima and did not contribute to the intimal hyperplasia. Rather, as shown by transplantation of labeled cells, adventitial progenitor cells seemed to be a prominent source of host-derived cells in the lesion, and MCP-1 exhibits an important role in their recruitment and the pathological process of intimal hyperplasia. Conclusions-The Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Transplantation of Allografts Leads to Structural Changes in Adjacent TissuesRejection of transplanted organs is associated with inflammation, and the production of factors that may activate cells in surrounding tissues. To determine how allografts influence the adjacent vessel tissues, we transplanted a fragment of rat isogenic (from F344 rats) or allogenic (from LEW rats) aortic graft into the abdominal aorta of F344 rats. Samples of aortic allografts and adjacent vessel segments were collected at 1, 2, 4, 8, and 12 weeks and analyzed separately; isograft samples were collected at 8 weeks.In 2-week-old allografts, immunohistochemical staining for α-smooth muscle actin was decreasing in the media, and α-smooth muscle actin positive cells had migrated to the neointima. Similar, but less prominent, changes were observed in adjacent vessels ( Figure 1A). At 1 to 2 weeks after transplantation, electron microscopy revealed distinct structural alterations in SMCs in the inner layer of the media and progressive de-endothelization of the allograft. Most of the SMCs were contracti...