Radiosensitivity of Vascular Tissue: II. Differential Radiosensitivity of Aortic Cells in Vitro

Fischer-Dzoga, Katti; Dimitrievich, George S.; Griem, Melvin L.

doi:10.2307/3576328

Cited by 55 publications

(18 citation statements)

References 10 publications

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“…As shown in Figure 1D, mean I/M ratio was significantly higher in BMT mice tended to be lower than those of Smad3-null and wild-type mice, respectively, presumably due to the effect of vascular irradiation. 35,36 Representative cross sections of BMT null3wild and BMT wild3null femoral arteries are shown in Figure 1E and 1F. …”

mentioning

confidence: 99%

Targeted Disruption of TGF-β–Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury

Kobayashi

Yokote

Fujimoto

et al. 2005

Circulation Research

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Abstract-The role of transforming growth factor (TGF)-␤ and its signal in atherogenesis is not fully understood. Here, we examined mice lacking Smad3, a major downstream mediator of TGF-␤, to clarify the precise role of Smad3-dependent signaling in vascular response to injury. Femoral arteries were injured in wild-type and Smad3-null (null) male mice on C57Bl/6 background. Histopathological evaluation of the arteries 1 to 3 weeks after the injury revealed significant enhancement of neointimal hyperplasia in null compared with wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating smooth muscle cells (SMC) with less amount of collagen compared with wild-type intima. TGF-␤ caused significant inhibition of cellular proliferation in wild-type aortic SMC, whereas the growth of null SMC was only weakly inhibited by TGF-␤ in vitro, indicating a crucial role of Smad3 in the growth inhibitory function. On the other hand, Smad3-deficiency did not attenuate chemotaxis of SMC toward TGF-␤. TGF-␤ increased transcript level of ␣2 type I collagen and tissue inhibitor of metalloproteinases-1, and suppressed expression and activity of matrix metalloproteinases in wild-type SMC. However, these effects of TGF-␤ were diminished in null SMC. Our findings altogether show that the loss of Smad3 pathway causes enhanced neointimal hyperplasia on injury through modulation of growth and matrix regulation in vascular SMC. These results indicate a vasculoprotective role of endogenous Smad3 in response to injury. Key Words: transforming growth factor-␤ Ⅲ Smad3 Ⅲ atherosclerosis Ⅲ neointimal hyperplasia Ⅲ smooth muscle cells T ransforming growth factor (TGF)-␤ is a prototypic member of the TGF-␤ superfamily that exerts a wide range of biological effects on various cell types. 1 Well described functions of TGF-␤ including growth inhibition, cell migration, differentiation, extracellular matrix production, and immunomodulation. Abnormality in TGF-␤ signaling may cause pathological conditions such as tumorigenesis, fibrotic disorders, and vascular diseases. 2 At present, however, the role of TGF-␤ and its signaling molecules in atherogenesis is not fully understood.TGF-␤ is often regarded to have proatherosclerotic effect on arteries. For example, TGF-␤ expression is increased in human restenotic lesions as well as in neointimal hyperplasia after balloon injury in animals. 3 TGF-␤ facilitates extracellular matrix deposition by stimulating production of procollagen and fibronectin, downregulating the expression of proteases, and upregulating protease inhibitors, such as plasminogen activator inhibitor type I (PAI-I) and tissue inhibitor of metalloproteinase-1 (TIMP-1). 4 -8 TGF-␤ transgene into vascular wall causes fibroproliferative intimal thickening in animal models in the presence or absence of vascular injury. 9,10 Moreover, TGF-␤ antagonism by antibody, soluble receptor, or ...

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confidence: 99%

Targeted Disruption of TGF-β–Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury

Kobayashi

Yokote

Fujimoto

et al. 2005

Circulation Research

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“…Weder Endothel-noch glatte Muskelzellen zeichnen sich durch eine auBergew0hnliche Strahlenreaktion aus [5,47] Insgesamt ist die Vulnerabilit5t einzelner Zellen entscheidend von der Zellzyklusphase abh~ngig [11,54]. Um die Strahlenbiologie besser verstehen zu k6nnen, ist es jedoch wichtig, genaue Dosisfindungsstudien durchzufª [2].…”

Section: Strahlenbioiogieunclassified

“…Experimentelle Arbeiten zeigen, daB die Zellen besonders in der G2/M-Zellteilungsphase empfindtich sind [11,12,22]. Es ist jedoch unktar, wann die verletzten Intimazellen der Gef~6wand in die proliferative Phase eintreten.…”

Section: Dosis-wirkungs-beziehungunclassified

Die intravasale Strahlenbehandlung zur kombinierten Therapie und Prävention der Restenosierung

Baumgart

Quast

Erbel

1997

Herz

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Despite numerous efforts in catheter technology and procedural approaches the problem of restenosis in interventional cardiology persists. Although the implantation of coronary stents has significantly reduced restenosis rates based on the inhibition of elastic recoil, intimal proliferation as the second major mechanism for postinterventional restenosis could not effectively be suppressed. Intimal proliferation is the response to vessel injury following interventional procedure, e.g. balloon angioplasty. It results in the adhesion of mono- and lymphocytes which themselves trigger the colonisation of myofibroblasts. Intracoronary irradiation seeks to prevent this proliferative process as it destroys or irreversibly alters DNA structures of cells at the site of balloon injury. The antiproliferative effect depends on the irradiation dosis, the timing and the cell cycle phase. Mainly beta- and gamma-radiation is used for intracoronary irradiation. Beta-emitters are characterized by a sharp decline of dose rate within millimeters from the actual source. The exposure to surrounding tissue as well the catheter staff can be kept to a minimum. The high intensity of beta-emitters allow a short treatment period of minutes to gain an effective radiation dose to the target. In contrast, gamma-emitters have a low radial dose distribution resulting in high dosage even centimeters away from the source. These emitters require additional shielding in the catheter laboratory and lead to excessive whole body doses. To achieve a sufficient dose in the target tissue, irradiation times of more than 20 minutes are necessary which prolongs the interventional procedure substantially. At present, catheter based systems or radioactive implantable stents are available to deliver the required dose. Catheter based systems seem more flexible in a number of considerations. On the other hand they require a substantial amount of hardware. Beta-emitting stents are implanted via a conventional stent delivery system with small shielding modifications. However, stents emit an inhomogeneous radiation profile due to the mesh-like structure. In addition, not every lesion can be reached by a stent nor does every lesion require a stent solely to deliver radiation. External irradiation is presently not recommended due to its ineffectiveness and the high rate of side effects. In the experimental setting the porcine model comes closest to the clinical situation in man. Animal experiments have demonstrated the effective reduction of intimal proliferation using beta- and gamma-sources in a wide dose range of 3 to 56 Gy. Although the initial and early results are convincing little is know about the long term results. Only few studies have been and are currently performed in patients. Some of these investigations demonstrate a significant reduction of restenosis rate after 6 months. Again, information on long-term results are lacking. It has to be considered that perivascular fibrosis, which may occur with a delay of 5 to 10 years depending on the dosage, could c...

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“…13,14,15,16 In vitro studies had demonstrated the inhibition of proliferation of arterial smooth muscle cells (SMC's) and fibroblasts as well as decreased collagen synthesis by fibroblasts. 17,18,19 The development of the porcine overstretch balloon injury model of restenosis has provided an excellent model in which to evaluate new therapies since as radiation. 20 In this animal model one or more of the coronary vessels are subjected to overstretch balloon injury and at two weeks, four weeks or six months the animal is sacrificed and the vessels harvested.…”

Section: Introductionmentioning

confidence: 99%

Radiation therapy to prevent coronary artery restenosis

Crocker

1999

Seminars in Radiation Oncology

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Radiosensitivity of Vascular Tissue: II. Differential Radiosensitivity of Aortic Cells in Vitro

Cited by 55 publications

References 10 publications

Targeted Disruption of TGF-β–Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury

Targeted Disruption of TGF-β–Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury

Die intravasale Strahlenbehandlung zur kombinierten Therapie und Prävention der Restenosierung

Radiation therapy to prevent coronary artery restenosis

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