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Yi-xin Wang - One of the best experts on this subject based on the ideXlab platform.

  • Mechanisms of intimal hyperplasia learned from a murine Carotid Artery Ligation model.
    Current vascular pharmacology, 2008
    Co-Authors: Le-ning Zhang, John F. Parkinson, Christopher Haskell, Yi-xin Wang
    Abstract:

    The murine Carotid Artery Ligation (CAL) model has been widely used in the research of intimal hyperplasia, a major pathological process in vascular diseases, such as atherosclerosis and restenosis after angioplasty. Using a variety of gene knockout or transgenic mice and different pharmacological interventions, these studies have yielded significant new findings that contribute not only to unraveling the basic molecular mechanisms involved in the pathogenesis of intimal hyperplasia, but also to the identification of novel targets for intervention of these diseases. The current review outlines the findings derived from the murine CAL model, including studies run by the authors, covering the impacts of hyperlipidemia, pro-inflammatory factors, endothelial dysfunction, protease activity and growth mediators on neointimal hyperplasia.

  • Monocyte chemoattractant protein-1 or macrophage inflammatory protein-1α deficiency does not affect angiotensin II-induced intimal hyperplasia in Carotid Artery Ligation model
    Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 2007
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Ronald Vergona, John C. Rutledge, Mark Sullivan, Yi-xin Wang
    Abstract:

    Abstract Background Angiotensin II (Ang II) promotes atherosclerotic vascular diseases, in which proinflammatory and proliferative effects play a major pathogenic role. Ang II up-regulates chemokines, such as monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α, which are important pro-inflammatory factors mediating infiltration of inflammatory cells into atherosclerotic lesion. The aim of the present study was to determine whether the presence of MCP-1 or MIP-1α is essential in Ang II-induced intimal hyperplasia in the Carotid Artery Ligation model. Methods Six-month-old male C57BL/6-, MCP-1-, or MIP-1α-deficient mice underwent Ligation of the common left Carotid Artery and were randomly assigned to receive either vehicle or Ang II (1.4 mg kg −1 day −1 ) via a subcutaneously implanted osmotic infusion pump (model 2004, Alzet) for 4 weeks. Results Ang II not only increased MCP-1 and MIP-1α production but also enhanced neo-intimal formation, media thickness, and adventitia development in the ligated Carotid arteries in C57BL/6 mice. However, MCP-1 or MIP-1α deficiency failed to affect intimal hyperplasia in vascular remodeling. Conclusion These results indicate that MCP-1 or MIP-1α may not be essential in mediating the proliferative effects of Ang II, a major pathological changes in intimal hyperplasia in the Carotid Artery Ligation model.

  • urokinase type plasminogen activator deficiency upa ko prevented Carotid Artery Ligation induced vascular remodeling in mice
    Translational Research, 2007
    Co-Authors: Baby Martinmcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Jon Vincelette, M Sullivan, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Urokinase-type plasminogen activator deficiency (uPA–KO) prevented Carotid Artery Ligation-induced vascular remodeling in mice
    Translational research : the journal of laboratory and clinical medicine, 2007
    Co-Authors: Baby Martin-mcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Mark Sullivan, Jon Vincelette, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-Derived Factor-1α in a Mouse Model of Carotid Artery Ligation
    Arteriosclerosis thrombosis and vascular biology, 2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    Background— Endothelial NO deficiency (endothelial NO synthase [eNOS]–knockout [KO]) enhanced smooth muscle cell (SMC)–rich neointimal lesion formation in a mouse model of Carotid Artery Ligation (CAL). Recent evidence indicated that stromal cell-derived factor-1α (SDF-1α)–mediated recruitment of circulating SMC progenitor cells substantially contributed to the SMC-rich neointimal hyperplasia induced by vascular injury. The goal of this study was to investigate the effects of eNOS deficiency on the expression of SDF-1α and mobilization of circulating SMC progenitor cells in CAL model. Methods and Results— Two- to 3-month-old C57BL/6J wild-type (WT) and eNOS-KO mice were evaluated 1, 2, or 4 weeks after CAL. CAL-induced expression of SDF-1α, as detected by immunohistochemical staining and further quantified by ELISA in the ligated Carotid arteries, was moderate and transient with a peak at 1 week in WT mice. SDF-1α expression was significantly higher at 1 week and persisted through 2 weeks in eNOS-KO mice. CAL was associated with increased circulating stem cell antigen-1+ (Sca-1 + )/c-Kit − /Lin − cells (interpreted as SMC progenitor cells), which peaked at 1 week in WT mice. This effect was also significantly greater and longer-lasting in eNOS-KO than WT mice. The number of circulating Sca-1 + /c-Kit − /Lin − cells was positively correlated with the expression of SDF-1α but not vascular endothelial growth factor in the ligated Carotid arteries. Furthermore, immunostaining showed abundant Sca-1–positive cells in the adventitia of the 1-week ligated Carotid arteries from eNOS-KO mice but not in WT mice. We also determined that eNOS deficiency enhanced CAL-induced intimal cell proliferation in the ligated arteries as detected by proliferating cell nuclear antigen staining but did not induce cell apoptosis as detected by staining for active caspase-3. Conclusion— Our results indicate that eNOS deficiency exacerbates CAL-induced expression of SDF-1α and its receptor CXCR4. This is correlated with an increase in Sca-1 + cells in peripheral blood and adventitia, which may contribute to vascular remodeling and SMC-rich neointimal lesion formation. This suggests that constitutive eNOS inhibits SDF-1α expression and provides an important vasculoprotective mechanism for intact endothelium to limit SMC proliferation and recruitment in response to vascular injury.

Valdeci Da Cunha - One of the best experts on this subject based on the ideXlab platform.

  • Monocyte chemoattractant protein-1 or macrophage inflammatory protein-1α deficiency does not affect angiotensin II-induced intimal hyperplasia in Carotid Artery Ligation model
    Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 2007
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Ronald Vergona, John C. Rutledge, Mark Sullivan, Yi-xin Wang
    Abstract:

    Abstract Background Angiotensin II (Ang II) promotes atherosclerotic vascular diseases, in which proinflammatory and proliferative effects play a major pathogenic role. Ang II up-regulates chemokines, such as monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α, which are important pro-inflammatory factors mediating infiltration of inflammatory cells into atherosclerotic lesion. The aim of the present study was to determine whether the presence of MCP-1 or MIP-1α is essential in Ang II-induced intimal hyperplasia in the Carotid Artery Ligation model. Methods Six-month-old male C57BL/6-, MCP-1-, or MIP-1α-deficient mice underwent Ligation of the common left Carotid Artery and were randomly assigned to receive either vehicle or Ang II (1.4 mg kg −1 day −1 ) via a subcutaneously implanted osmotic infusion pump (model 2004, Alzet) for 4 weeks. Results Ang II not only increased MCP-1 and MIP-1α production but also enhanced neo-intimal formation, media thickness, and adventitia development in the ligated Carotid arteries in C57BL/6 mice. However, MCP-1 or MIP-1α deficiency failed to affect intimal hyperplasia in vascular remodeling. Conclusion These results indicate that MCP-1 or MIP-1α may not be essential in mediating the proliferative effects of Ang II, a major pathological changes in intimal hyperplasia in the Carotid Artery Ligation model.

  • urokinase type plasminogen activator deficiency upa ko prevented Carotid Artery Ligation induced vascular remodeling in mice
    Translational Research, 2007
    Co-Authors: Baby Martinmcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Jon Vincelette, M Sullivan, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Urokinase-type plasminogen activator deficiency (uPA–KO) prevented Carotid Artery Ligation-induced vascular remodeling in mice
    Translational research : the journal of laboratory and clinical medicine, 2007
    Co-Authors: Baby Martin-mcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Mark Sullivan, Jon Vincelette, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-Derived Factor-1α in a Mouse Model of Carotid Artery Ligation
    Arteriosclerosis thrombosis and vascular biology, 2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    Background— Endothelial NO deficiency (endothelial NO synthase [eNOS]–knockout [KO]) enhanced smooth muscle cell (SMC)–rich neointimal lesion formation in a mouse model of Carotid Artery Ligation (CAL). Recent evidence indicated that stromal cell-derived factor-1α (SDF-1α)–mediated recruitment of circulating SMC progenitor cells substantially contributed to the SMC-rich neointimal hyperplasia induced by vascular injury. The goal of this study was to investigate the effects of eNOS deficiency on the expression of SDF-1α and mobilization of circulating SMC progenitor cells in CAL model. Methods and Results— Two- to 3-month-old C57BL/6J wild-type (WT) and eNOS-KO mice were evaluated 1, 2, or 4 weeks after CAL. CAL-induced expression of SDF-1α, as detected by immunohistochemical staining and further quantified by ELISA in the ligated Carotid arteries, was moderate and transient with a peak at 1 week in WT mice. SDF-1α expression was significantly higher at 1 week and persisted through 2 weeks in eNOS-KO mice. CAL was associated with increased circulating stem cell antigen-1+ (Sca-1 + )/c-Kit − /Lin − cells (interpreted as SMC progenitor cells), which peaked at 1 week in WT mice. This effect was also significantly greater and longer-lasting in eNOS-KO than WT mice. The number of circulating Sca-1 + /c-Kit − /Lin − cells was positively correlated with the expression of SDF-1α but not vascular endothelial growth factor in the ligated Carotid arteries. Furthermore, immunostaining showed abundant Sca-1–positive cells in the adventitia of the 1-week ligated Carotid arteries from eNOS-KO mice but not in WT mice. We also determined that eNOS deficiency enhanced CAL-induced intimal cell proliferation in the ligated arteries as detected by proliferating cell nuclear antigen staining but did not induce cell apoptosis as detected by staining for active caspase-3. Conclusion— Our results indicate that eNOS deficiency exacerbates CAL-induced expression of SDF-1α and its receptor CXCR4. This is correlated with an increase in Sca-1 + cells in peripheral blood and adventitia, which may contribute to vascular remodeling and SMC-rich neointimal lesion formation. This suggests that constitutive eNOS inhibits SDF-1α expression and provides an important vasculoprotective mechanism for intact endothelium to limit SMC proliferation and recruitment in response to vascular injury.

  • Endothelial nitric oxide synthase deficiency enhanced Carotid Artery Ligation-induced remodeling by promoting vascular inflammation
    2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    sis, vessel inflammation, remodeling, eNOS knockout mice, nitric oxide, smooth muscle cell, monocyte chemoat- tractant protein-1, vascular cell adhe- sion molecule-1, macrophage ABSTRACT Nitric oxide (NO) plays an important role in vascular protection. It has been reported that endothelial NO synthase (eNOS) deficiency exacerbated Carotid Artery Ligation (CAL)-induced vascular remodeling, which, however, did not elu- cidate the role of inflammation. Over- expression of eNOS inhibited vascular inflammation and remodeling in a CAL model. However, there is no study that tested the hypothesis that eNOS defi- ciency can enhance the inflammatory 100

Ronald Vergona - One of the best experts on this subject based on the ideXlab platform.

  • Monocyte chemoattractant protein-1 or macrophage inflammatory protein-1α deficiency does not affect angiotensin II-induced intimal hyperplasia in Carotid Artery Ligation model
    Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 2007
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Ronald Vergona, John C. Rutledge, Mark Sullivan, Yi-xin Wang
    Abstract:

    Abstract Background Angiotensin II (Ang II) promotes atherosclerotic vascular diseases, in which proinflammatory and proliferative effects play a major pathogenic role. Ang II up-regulates chemokines, such as monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α, which are important pro-inflammatory factors mediating infiltration of inflammatory cells into atherosclerotic lesion. The aim of the present study was to determine whether the presence of MCP-1 or MIP-1α is essential in Ang II-induced intimal hyperplasia in the Carotid Artery Ligation model. Methods Six-month-old male C57BL/6-, MCP-1-, or MIP-1α-deficient mice underwent Ligation of the common left Carotid Artery and were randomly assigned to receive either vehicle or Ang II (1.4 mg kg −1 day −1 ) via a subcutaneously implanted osmotic infusion pump (model 2004, Alzet) for 4 weeks. Results Ang II not only increased MCP-1 and MIP-1α production but also enhanced neo-intimal formation, media thickness, and adventitia development in the ligated Carotid arteries in C57BL/6 mice. However, MCP-1 or MIP-1α deficiency failed to affect intimal hyperplasia in vascular remodeling. Conclusion These results indicate that MCP-1 or MIP-1α may not be essential in mediating the proliferative effects of Ang II, a major pathological changes in intimal hyperplasia in the Carotid Artery Ligation model.

  • urokinase type plasminogen activator deficiency upa ko prevented Carotid Artery Ligation induced vascular remodeling in mice
    Translational Research, 2007
    Co-Authors: Baby Martinmcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Jon Vincelette, M Sullivan, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Urokinase-type plasminogen activator deficiency (uPA–KO) prevented Carotid Artery Ligation-induced vascular remodeling in mice
    Translational research : the journal of laboratory and clinical medicine, 2007
    Co-Authors: Baby Martin-mcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Mark Sullivan, Jon Vincelette, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-Derived Factor-1α in a Mouse Model of Carotid Artery Ligation
    Arteriosclerosis thrombosis and vascular biology, 2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    Background— Endothelial NO deficiency (endothelial NO synthase [eNOS]–knockout [KO]) enhanced smooth muscle cell (SMC)–rich neointimal lesion formation in a mouse model of Carotid Artery Ligation (CAL). Recent evidence indicated that stromal cell-derived factor-1α (SDF-1α)–mediated recruitment of circulating SMC progenitor cells substantially contributed to the SMC-rich neointimal hyperplasia induced by vascular injury. The goal of this study was to investigate the effects of eNOS deficiency on the expression of SDF-1α and mobilization of circulating SMC progenitor cells in CAL model. Methods and Results— Two- to 3-month-old C57BL/6J wild-type (WT) and eNOS-KO mice were evaluated 1, 2, or 4 weeks after CAL. CAL-induced expression of SDF-1α, as detected by immunohistochemical staining and further quantified by ELISA in the ligated Carotid arteries, was moderate and transient with a peak at 1 week in WT mice. SDF-1α expression was significantly higher at 1 week and persisted through 2 weeks in eNOS-KO mice. CAL was associated with increased circulating stem cell antigen-1+ (Sca-1 + )/c-Kit − /Lin − cells (interpreted as SMC progenitor cells), which peaked at 1 week in WT mice. This effect was also significantly greater and longer-lasting in eNOS-KO than WT mice. The number of circulating Sca-1 + /c-Kit − /Lin − cells was positively correlated with the expression of SDF-1α but not vascular endothelial growth factor in the ligated Carotid arteries. Furthermore, immunostaining showed abundant Sca-1–positive cells in the adventitia of the 1-week ligated Carotid arteries from eNOS-KO mice but not in WT mice. We also determined that eNOS deficiency enhanced CAL-induced intimal cell proliferation in the ligated arteries as detected by proliferating cell nuclear antigen staining but did not induce cell apoptosis as detected by staining for active caspase-3. Conclusion— Our results indicate that eNOS deficiency exacerbates CAL-induced expression of SDF-1α and its receptor CXCR4. This is correlated with an increase in Sca-1 + cells in peripheral blood and adventitia, which may contribute to vascular remodeling and SMC-rich neointimal lesion formation. This suggests that constitutive eNOS inhibits SDF-1α expression and provides an important vasculoprotective mechanism for intact endothelium to limit SMC proliferation and recruitment in response to vascular injury.

  • Endothelial nitric oxide synthase deficiency enhanced Carotid Artery Ligation-induced remodeling by promoting vascular inflammation
    2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    sis, vessel inflammation, remodeling, eNOS knockout mice, nitric oxide, smooth muscle cell, monocyte chemoat- tractant protein-1, vascular cell adhe- sion molecule-1, macrophage ABSTRACT Nitric oxide (NO) plays an important role in vascular protection. It has been reported that endothelial NO synthase (eNOS) deficiency exacerbated Carotid Artery Ligation (CAL)-induced vascular remodeling, which, however, did not elu- cidate the role of inflammation. Over- expression of eNOS inhibited vascular inflammation and remodeling in a CAL model. However, there is no study that tested the hypothesis that eNOS defi- ciency can enhance the inflammatory 100

John C. Rutledge - One of the best experts on this subject based on the ideXlab platform.

  • Monocyte chemoattractant protein-1 or macrophage inflammatory protein-1α deficiency does not affect angiotensin II-induced intimal hyperplasia in Carotid Artery Ligation model
    Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 2007
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Ronald Vergona, John C. Rutledge, Mark Sullivan, Yi-xin Wang
    Abstract:

    Abstract Background Angiotensin II (Ang II) promotes atherosclerotic vascular diseases, in which proinflammatory and proliferative effects play a major pathogenic role. Ang II up-regulates chemokines, such as monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α, which are important pro-inflammatory factors mediating infiltration of inflammatory cells into atherosclerotic lesion. The aim of the present study was to determine whether the presence of MCP-1 or MIP-1α is essential in Ang II-induced intimal hyperplasia in the Carotid Artery Ligation model. Methods Six-month-old male C57BL/6-, MCP-1-, or MIP-1α-deficient mice underwent Ligation of the common left Carotid Artery and were randomly assigned to receive either vehicle or Ang II (1.4 mg kg −1 day −1 ) via a subcutaneously implanted osmotic infusion pump (model 2004, Alzet) for 4 weeks. Results Ang II not only increased MCP-1 and MIP-1α production but also enhanced neo-intimal formation, media thickness, and adventitia development in the ligated Carotid arteries in C57BL/6 mice. However, MCP-1 or MIP-1α deficiency failed to affect intimal hyperplasia in vascular remodeling. Conclusion These results indicate that MCP-1 or MIP-1α may not be essential in mediating the proliferative effects of Ang II, a major pathological changes in intimal hyperplasia in the Carotid Artery Ligation model.

  • urokinase type plasminogen activator deficiency upa ko prevented Carotid Artery Ligation induced vascular remodeling in mice
    Translational Research, 2007
    Co-Authors: Baby Martinmcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Jon Vincelette, M Sullivan, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Urokinase-type plasminogen activator deficiency (uPA–KO) prevented Carotid Artery Ligation-induced vascular remodeling in mice
    Translational research : the journal of laboratory and clinical medicine, 2007
    Co-Authors: Baby Martin-mcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Mark Sullivan, Jon Vincelette, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-Derived Factor-1α in a Mouse Model of Carotid Artery Ligation
    Arteriosclerosis thrombosis and vascular biology, 2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    Background— Endothelial NO deficiency (endothelial NO synthase [eNOS]–knockout [KO]) enhanced smooth muscle cell (SMC)–rich neointimal lesion formation in a mouse model of Carotid Artery Ligation (CAL). Recent evidence indicated that stromal cell-derived factor-1α (SDF-1α)–mediated recruitment of circulating SMC progenitor cells substantially contributed to the SMC-rich neointimal hyperplasia induced by vascular injury. The goal of this study was to investigate the effects of eNOS deficiency on the expression of SDF-1α and mobilization of circulating SMC progenitor cells in CAL model. Methods and Results— Two- to 3-month-old C57BL/6J wild-type (WT) and eNOS-KO mice were evaluated 1, 2, or 4 weeks after CAL. CAL-induced expression of SDF-1α, as detected by immunohistochemical staining and further quantified by ELISA in the ligated Carotid arteries, was moderate and transient with a peak at 1 week in WT mice. SDF-1α expression was significantly higher at 1 week and persisted through 2 weeks in eNOS-KO mice. CAL was associated with increased circulating stem cell antigen-1+ (Sca-1 + )/c-Kit − /Lin − cells (interpreted as SMC progenitor cells), which peaked at 1 week in WT mice. This effect was also significantly greater and longer-lasting in eNOS-KO than WT mice. The number of circulating Sca-1 + /c-Kit − /Lin − cells was positively correlated with the expression of SDF-1α but not vascular endothelial growth factor in the ligated Carotid arteries. Furthermore, immunostaining showed abundant Sca-1–positive cells in the adventitia of the 1-week ligated Carotid arteries from eNOS-KO mice but not in WT mice. We also determined that eNOS deficiency enhanced CAL-induced intimal cell proliferation in the ligated arteries as detected by proliferating cell nuclear antigen staining but did not induce cell apoptosis as detected by staining for active caspase-3. Conclusion— Our results indicate that eNOS deficiency exacerbates CAL-induced expression of SDF-1α and its receptor CXCR4. This is correlated with an increase in Sca-1 + cells in peripheral blood and adventitia, which may contribute to vascular remodeling and SMC-rich neointimal lesion formation. This suggests that constitutive eNOS inhibits SDF-1α expression and provides an important vasculoprotective mechanism for intact endothelium to limit SMC proliferation and recruitment in response to vascular injury.

  • Endothelial nitric oxide synthase deficiency enhanced Carotid Artery Ligation-induced remodeling by promoting vascular inflammation
    2006
    Co-Authors: Le Ning Zhang, Valdeci Da Cunha, Baby Martin-mcnulty, Dennis W Wilson, Mark E. Sullivan, Ronald Vergona, John C. Rutledge, Yi-xin Wang
    Abstract:

    sis, vessel inflammation, remodeling, eNOS knockout mice, nitric oxide, smooth muscle cell, monocyte chemoat- tractant protein-1, vascular cell adhe- sion molecule-1, macrophage ABSTRACT Nitric oxide (NO) plays an important role in vascular protection. It has been reported that endothelial NO synthase (eNOS) deficiency exacerbated Carotid Artery Ligation (CAL)-induced vascular remodeling, which, however, did not elu- cidate the role of inflammation. Over- expression of eNOS inhibited vascular inflammation and remodeling in a CAL model. However, there is no study that tested the hypothesis that eNOS defi- ciency can enhance the inflammatory 100

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  • Mechanisms of intimal hyperplasia learned from a murine Carotid Artery Ligation model.
    Current vascular pharmacology, 2008
    Co-Authors: Le-ning Zhang, John F. Parkinson, Christopher Haskell, Yi-xin Wang
    Abstract:

    The murine Carotid Artery Ligation (CAL) model has been widely used in the research of intimal hyperplasia, a major pathological process in vascular diseases, such as atherosclerosis and restenosis after angioplasty. Using a variety of gene knockout or transgenic mice and different pharmacological interventions, these studies have yielded significant new findings that contribute not only to unraveling the basic molecular mechanisms involved in the pathogenesis of intimal hyperplasia, but also to the identification of novel targets for intervention of these diseases. The current review outlines the findings derived from the murine CAL model, including studies run by the authors, covering the impacts of hyperlipidemia, pro-inflammatory factors, endothelial dysfunction, protease activity and growth mediators on neointimal hyperplasia.

  • urokinase type plasminogen activator deficiency upa ko prevented Carotid Artery Ligation induced vascular remodeling in mice
    Translational Research, 2007
    Co-Authors: Baby Martinmcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Jon Vincelette, M Sullivan, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.

  • Urokinase-type plasminogen activator deficiency (uPA–KO) prevented Carotid Artery Ligation-induced vascular remodeling in mice
    Translational research : the journal of laboratory and clinical medicine, 2007
    Co-Authors: Baby Martin-mcnulty, Le-ning Zhang, Valdeci Da Cunha, Ronald Vergona, John C. Rutledge, Mark Sullivan, Jon Vincelette, Yi-xin Wang
    Abstract:

    It has been demonstrated that urokinase-type plasminogen activator (uPA) plays an important role in vascular remodeling. This study was designed to determine whether uPA deficiency (KO) affects Carotid Artery Ligation-induced vessel remodeling and the interaction with angiotensin II (Ang II). Ligation of the left common Carotid Artery in 6-month-old wild-type (C57 black/6J) mice for 4 weeks induced a concentric remodeling with vessel wall thickening, characterized by cell proliferation in neointima, media, and adventitia, and with lumen narrowing without a significant enlargement of overall vessel dimension. Intima lesions were characterized by α-actin positive smooth muscle cell (SMC) proliferation in a matrix background. No detectable presence of MAC-3 positive macrophages existed in the vascular wall. The Ligation-induced vascular neointimal formation and adventitial proliferation, but not lumen narrowing and media expansion, were completely prevented in age-matched uPA–KO mice. Chronic infusion of Ang II (1.44 mg/kg per day) via a subcutaneously implanted osmotic minipump did not significantly affect the gross morphology of the nonligated Carotid Artery from both wild-type and uPA–KO mice, but it enhanced Ligation-induced vascular remodeling. However, in the presence of Ang II, uPA deficiency had no effects on Ligation-induced mophermetric change, but it partially and significantly reduced cell proliferation. These data indicate that uPA may play a critical role in Ligation-induced vessel remodeling. Ang II may activate other mechanisms independent of uPA to exacerbate Ligation-induced vascular remodeling.