Nitric Oxide–Induced Downregulation of Cdk2 Activity and Cyclin A Gene Transcription in Vascular Smooth Muscle Cells

Guo, Kun; Andrés, Vicente; Walsh, Kenneth

doi:10.1161/01.cir.97.20.2066

Cited by 82 publications

(54 citation statements)

References 43 publications

(37 reference statements)

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“…26,27 Although the mechanisms are still not fully elucidated, recent reports have implicated that NO affects some cell cycle-associated proteins, such as cyclin A. 28 In the present study, overexpression of eNOS in the endothelium reduced neointimal and medial thickening but did not affect the reduction in vessel diameter. The mechanisms of vascular constriction in this model are unclear, and so far, only the participation of the cytoskeleton 29 and the role of iNOS detected in the adventitia and the outer layer have been suggested.…”

Section: Discussionsupporting

confidence: 42%

Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling

Kawashima

Yamashita

Ozaki

et al. 2001

ATVB

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Abstract-NO produced by endothelial NO synthase (eNOS) plays important roles in the regulation of vascular tone and structure. The purpose of this study was to clarify the role of eNOS-derived NO on vascular remodeling by use of eNOS-transgenic (eNOS-Tg) mice. The common carotid artery was ligated just proximal to the carotid bifurcation. Four weeks later, the proximal carotid artery of the ligation site was histologically examined. In this vascular remodeling model, the endothelium remains uninjured, but neointimal and medial thickening occurs in combination with a reduction in vascular diameter at the proximal portion of the ligation. At 4 weeks after ligation, the respective neointimal and medial areas in wild-type mice were 17 200Ϯ1100 and 24 300Ϯ1500 m 2 , whereas both were reduced to 8000Ϯ1900 (PϽ0.01) and 18 400Ϯ700 m 2 (PϽ0.01) in eNOS-Tg mice (nϭ8). Total vascular area was not different between the 2 genotypes. N G -Nitro-L-arginine methyl ester treatment increased neointimal and medial areas to the same extent in both genotypes. Leukocyte infiltration was observed in the luminal side of the vessel, but the number of infiltrating cells was significantly attenuated in eNOS-Tg mice compared with wild-type mice. This reduction of leukocyte infiltration in eNOS-Tg mice was associated with reduced expressions of intracellular adhesion molecule-1 and vascular cellular adhesion molecule-1 on the endothelium. In conclusion, chronic eNOS overexpression in the endothelium reduced leukocyte infiltration and inhibited neointimal formation and medial thickening. Our data provide the evidence for the regulatory role of NO from the endothelium on vascular structure integrity. V ascular remodeling is an adaptive process that occurs in response to chronic changes in blood flow and other hemodynamic conditions, and a variety of vascular cellular responses, such as the growth and death of vascular smooth muscle cells and changes in extracellular matrix composition, are involved in the mechanisms. 1,2 Endothelial cells are thought to play a cardinal role in sensing changes in mechanical and biochemical forces and to regulate vascular structure. 3 One of the key molecules released by the endothelium is NO, synthesized by endothelial NO synthase (eNOS), which diffuses to underlying vascular smooth muscle cells or the lumen side and affects various cell functions. Over the past years, several studies have been performed involving the importance of endogenous eNOS-derived NO in vascular remodeling with the use of NO synthase (NOS) inhibitortreated animals and eNOS-deficient mice. 4 -6 Furthermore, eNOS gene transfer to the balloon-injured arteries in animal experiments has been shown to inhibit neointimal formation. 7-9 However, in those studies, eNOS was overexpressed mainly in vascular smooth muscle cells and/or the adventitia, not in the endothelium. On the other hand, no studies have ever tried to examine the effect of chronic overproduction of eNOS-derived NO from the endothelium on vascular remodeling. Recently, we gener...

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Section: Discussionsupporting

confidence: 42%

Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling

Kawashima

Yamashita

Ozaki

et al. 2001

ATVB

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“…This is, at least in part, due to NO inhibition of medial SMC proliferation (77). Recent studies reveal that NO inhibition of SMC growth is regulated by its ability to down-regulate Cdk2 and cyclin A gene transcription (79). The capacity of NO to suppress the expression of PDGF-A (in the present study), which is chemotactic for SMC (80), is consistent with the ability of NO to inhibit SMC migration through the AT1 receptor (6).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

Day

Rafty

Chesterman

et al. 1999

Journal of Biological Chemistry

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Angiotensin II (ATII) and platelet-derived growth factor (PDGF) are two vasoconstrictors implicated in the maintenance of normal vascular homeostasis. PDGF Achain levels increase in cultured vascular smooth muscle cells (SMCs) exposed to ATII. The molecular mechanisms underlying this induction are not known. We used transient transfection analysis to show that ATII can increase reporter gene activity driven by fragments of the PDGF-A promoter bearing recognition elements for the transcription factor, Egr-1. Nuclear run-off experiments indicate that ATII induces Egr-1 expression at the level of transcription. Gel shift and supershift studies show that Egr-1 protein accumulates in the nuclei of SMCs exposed to ATII and binds to the proximal region of the PDGF-A promoter in a specific, time-dependent manner. ATII induced extracellular-signal regulated kinase (p42/44 ERK) activity as did phorbol 12-myristate 13-acetate. The specific MEK1/2 inhibitor, PD98059, suppressedbothPDGF-AandEgr-1endogenousandpromoter-dependent expression inducible by ATII. The ATII type 1 receptor (AT1) antagonist, Losartan, inhibited ATII-induction of p42/44 ERK, as well as Egr-1 and PDGF-A, whereas neither PD123319, an AT2 receptor antagonist, nor wortmannin, an inhibitor of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase, had any effect. ATII-induction of Egr-1 and PDGF-A was blocked by SIN-1, a NO donor. In addition, this pathway was blocked by overexpression of NO synthase. Collectively, these findings demonstrate that ATII activation of the PDGF-A promoter is mediated via the MEK/ERK/Egr-1 pathway and AT1 receptor and that this process is antagonized by NO.Angiotensin II (ATII), 1 a peptide hormone with potent vasoconstrictor activity, has long been implicated in the pathobiology of hypertension. In vascular smooth muscle cells (SMCs), ATII stimulates protein synthesis (1), cellular hypertrophy (2-5), migration (6), extracellular matrix synthesis (7,8), and the activation of a large number of transcription factors. These include Jak/STAT (9), Ets-1 (10), SRF (11), MHox (11), c-Jun (12, 13), JunB (12), and c-Fos (14). ATII is produced in the vessel wall by the actions of renin, which converts angiotensinogen to ATI, which is then cleaved to ATII by angiotensin-converting enzyme. Two ATII receptor subtypes have been described, AT1 and AT2. Signal transduction through G-protein-coupled AT1 receptors involves phospholipase C, phospholipase A 2 , phospholipase D, adenylate cyclase, and the release of intracellular calcium (reviewed in Refs. 15 and 16). The AT1 receptor also regulates neointimal thickening after mechanical injury to the rat carotid artery wall and ATII infusion (17). AT2 receptor signaling is less well understood, but evidence suggests that this receptor is involved in growth inhibition (18), Bcl-2 dephosphorylation (19), and apoptosis (20, 21). Platelet-derived growth factor (PDGF) consists of an A-chain and B-chain held together in homo-or heterodimeric configuration by disulfide bonds (reviewed in Refs. 22 and 2...

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“…The endothelium normally provides a nonpermeable barrier to protect VSMCs against the effect of circulating growth factors (12). The endothelium also produces nitric oxide, which has several antimitogenic properties (13,14). Nitric oxide has been shown to downregulate cyclin-dependent kinase (CDK) 2 and cyclin A and upregulate p21, resulting in cell cycle arrest (14).…”

Section: Vessel Wall Injurymentioning

confidence: 99%

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

Charron

Nili

Strauss

2006

Canadian Journal of Cardiology

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Nitric Oxide–Induced Downregulation of Cdk2 Activity and Cyclin A Gene Transcription in Vascular Smooth Muscle Cells

Cited by 82 publications

References 43 publications

Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling

Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

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