The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation

Shibata, Masayuki; Suzuki, Hiroshi; Nakatani, Masaki; Koba, Shinji; Geshi, Eiichi; Kubo, Takashi; Takeyama, Youichi

doi:10.1007/s00418-001-0336-4

Cited by 51 publications

(45 citation statements)

References 24 publications

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“…For example, intraplaque neovascularization is a common feature of atherosclerosis, and many proangiogenic factors are found in human atherosclerotic lesions (17). Increased adventitial neovascularization is also seen at sites of neointimal hyperplasia following arterial or venous stenting (34). Inflammatory cells and SMC within lesions are important local sources of proangiogenic factors (21).…”

Section: Discussionmentioning

confidence: 99%

“…TVS development involves chronic perivascular inflammation, EC dysfunction, and SMC migration/proliferation, resulting in neointimal thickening of the allograft arterial wall (1,12,22). A growing body of evidence supports a role for angiogenesis (AG) and wound healing (WH) in the development of vascular diseases (17,34). Importantly, pathological processes involved in TVS and other vascular diseases parallel many cellular events that mediate normal AG/WH.…”

mentioning

confidence: 99%

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Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Dumortier

Streblow

Moses

et al. 2008

J Virol

103

102

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Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.Numerous epidemiological and animal studies link human cytomegalovirus (HCMV) to the acceleration of vascular diseases including arterial restenosis, atherosclerosis, and transplant vascular sclerosis (TVS) (23,24,37). Recent advances in transplantation have significantly impacted short-term allograft and patient survival; however, long-term graft survival has not improved, due largely to chronic rejection (CR). The prevalence of CR is a concern, since retransplantation is the sole effective therapy. TVS represents the hallmark of CR in vascularized solid organ transplants, and HCMV infection nearly doubles the 5-year rate of cardiac graft failure due to accelerated TVS (11). In heart transplant recipients, ganciclovir, a potent inhibitor of CMV replication, delays the time to allograft rejection (25, 44). A higher incidence of viral DNA in the explant vascular intima from patients with cardiac allograft TVS than in explants without vasculopathy further underscores the influence of HCMV on CR development (47). In kidney transplant patients, the presence of HCMV infection, whether asymptomatic or displaying overt symptoms, negatively impacts allograft survival (9). The role of HCMV in TVS/CR development is clear; however, the mechanisms involved in this process remain illusive for the following reasons: HCMV disease etiology is multifactorial; HCMV is ubiquitous throughout the human population; HCMV infection is lifelong and infects all of the cell types involved in TVS, including smooth muscle cells (SMC), endothelial cells (EC), and macrophages; and HCMV evades the immune system by remaining latent, and clinically silent reactivation is diffic...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Dumortier

Streblow

Moses

et al. 2008

J Virol

103

102

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“…Hematoxylin and eosin (H&E), Verhoeff's van Gieson (VVG), PCNA, Masson's trichrome, VEGF-A, VEGFR-1, and ␣-smooth muscle actin staining were performed on the vein-to-graft anastomosis and control vein removed from animals on day 3 (n ϭ 3), day 7 (n ϭ 3), and day 14 (n ϭ 3) as previously described (35,54). The thickness of the intima, media, and adventitia of the vein-to-graft anastomosis and control vein was determined from sections stained with VVG stain and pooled together for each time point as previously described (35).…”

Section: Methodsmentioning

confidence: 99%

Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts

Misra¹,

Fu²,

Puggioni³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Venous injury and subsequent venous stenosis formation are responsible for hemodialysis graft failure. Our hypothesis is that these pathological changes are in part related to changes in wall shear stress (WSS) that results in the activation of matrix regulatory proteins causing subsequent venous stenosis formation. In the present study, we examined the serial changes in WSS, blood flow, and luminal vessel area that occur subsequent to the placement of a hemodialysis graft in a porcine model of chronic renal insufficiency. We then determined the corresponding histological, morphometric, and kinetic changes of several matrix regulatory proteins including VEGF-A, its receptors, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2. WSS was estimated by obtaining blood flow and luminal vessel area by performing phase-contrast MRI with magnetic resonance angiography in 21 animals at 1 day after graft placement and prior to death on day 3 ( n = 7), day 7 ( n = 7), and day 14 ( n = 7). At all time points, the mean WSS at the vein-to-graft anastomosis was significantly higher than that at the control vein ( P < 0.05). WSS had a bimodal distribution with peaks on days 1 and 7 followed by a significant reduction in WSS by day 14 ( P < 0.05 compared with day 7) and a decrease in luminal vessel area compared with control vessels. By day 3, there was a significant increase in VEGF-A and pro-MMP-9 followed by, on day 7, increased pro-MMP-2, active MMP-2, and VEGF receptor (VEGFR)-2 ( P < 0.05) and, by day 14, increased VEGFR-1 and TIMP-1 ( P < 0.05) at the vein-to-graft anastomosis compared with control vessels. Over time, the neointima thickened and was composed primarily of α-smooth muscle actin-positive cells with increased cellular proliferation. Our data suggest that hemodialysis graft placement leads to early increases in WSS, VEGF-A, and pro-MMP-9 followed by subsequent increases in pro-MMP-2, active MMP-2, VEGFR-1, VEGFR-2, and TIMP-1, which may contribute to the development of venous stenosis.

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“…Increased neovascularization has been observed at sites of intimal hyperplasia in models of arterial stenting, 62 angioplasty, 25,63 and venous bypass graft failure. 64,65 In pig coronary arteries, adventitial neovascularization correlated with vessel stenosis after balloon injury and stent implantation, and VEGF expression was reported after stenting.…”

Section: Role Of Angiogenesis In Neointimal Growthmentioning

confidence: 99%

Role of Angiogenesis in Cardiovascular Disease

et al. 2005

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Abstract-The role of angiogenesis in atherosclerosis and other cardiovascular diseases has emerged as a major unresolved issue. Angiogenesis has attracted interest from opposite perspectives. Angiogenic cytokine therapy has been widely regarded as an attractive approach both for treating ischemic heart disease and for enhancing arterioprotective functions of the endothelium; conversely, a variety of studies suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Here, we critically review the evidence supporting a role for angiogenesis and angiogenic factors in atherosclerosis and neointima formation, emphasizing the problems raised by some of the landmark studies and the suitability of animal models of atherosclerosis and neointimal thickening for investigating the role of angiogenesis. Because many of the relevant studies have focused on the role of vascular endothelial growth factor (VEGF), we consider this work in the wider context of VEGF biology and in light of recent experience from clinical trials of VEGF and other angiogenic cytokines for ischemic heart disease. Also discussed are recent findings suggesting that, although angiogenesis may contribute to neointimal growth, it is not required for the initiation of intimal thickening. Our assessment of the evidence leads us to conclude that, although microvessels are a feature of advanced human atherosclerotic plaques, it remains unclear whether angiogenesis either plays a central role in the development of atherosclerosis or is responsible for plaque instability. Furthermore, current evidence from clinical trials of both proangiogenic and antiangiogenic therapies does not suggest that inhibition of angiogenesis is likely to be a viable therapeutic strategy for cardiovascular disease.

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The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation

Cited by 51 publications

References 24 publications

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts

Role of Angiogenesis in Cardiovascular Disease

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