Effect of Platelet-Derived Growth Factor Receptor-α and -β Blockade on Flow-Induced Neointimal Formation in Endothelialized Baboon Vascular Grafts

Owens, Erik L.; Mason, David P.; Lea, Holly; Tran, Phan‐Kiet; Vergel, Selina; Hawkins, Suzanne; Hart, Charles E.; Clowes, Alexander W.

doi:10.1161/01.res.86.7.779

Cited by 40 publications

(44 citation statements)

References 43 publications

(42 reference statements)

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“…However, a discussion of ␣-vs. ␤-receptor roles is important. Although somewhat controversial, results from a number of in vitro studies have provided evidence that PDGF ␣-receptor signaling selectively mediates DNA and protein synthesis (20,37), but not migration (9), whereas PDGF ␤-receptor signaling induces DNA synthesis (20) and migration (9). Because of the receptor binding properties of PDGF-DD, it is interesting to speculate that perhaps PDGF-DD contributes to disease states where there is both migration and proliferation of ␤-receptorexpressing cells.…”

Section: Discussionmentioning

confidence: 99%

PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns

Thomas

Deaton²,

Hastings³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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GK. PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. Am J Physiol Heart Circ Physiol 296: H442-H452, 2009. First published November 21, 2008 doi:10.1152/ajpheart.00165.2008.-Platelet-derived growth factor (PDGF)-BB is a well-known smooth muscle (SM) cell (SMC) phenotypic modulator that signals by binding to PDGF ␣␣-, ␣␤-, and ␤␤-membrane receptors. PDGF-DD is a recently identified PDGF family member, and its role in SMC phenotypic modulation is unknown. Here we demonstrate that PDGF-DD inhibited expression of multiple SMC genes, including SM ␣-actin and SM myosin heavy chain, and upregulated expression of the potent SMC differentiation repressor gene Kruppel-like factor-4 at the mRNA and protein levels. On the basis of the results of promoter-reporter assays, changes in SMC gene expression were mediated, at least in part, at the level of transcription. Attenuation of the SMC phenotypic modulatory activity of PDGF-DD by pharmacological inhibitors of ERK phosphorylation and by a small interfering RNA to Kruppel-like factor-4 highlight the role of these two pathways in this process. PDGF-DD failed to repress SM ␣-actin and SM myosin heavy chain in mouse SMCs lacking a functional PDGF ␤-receptor. Importantly, PDGF-DD expression was increased in neointimal lesions in the aortic arch region of apolipoprotein C-deficient (ApoE Ϫ/Ϫ ) mice. Furthermore, human endothelial cells exposed to an atherosclerosis-prone flow pattern, as in vascular regions susceptible to the development of atherosclerosis, exhibited a significant increase in PDGF-DD expression. These findings demonstrate a novel activity for PDGF-DD in SMC biology and highlight the potential contribution of this molecule to SMC phenotypic modulation in the setting of disturbed blood flow. shear stress; disturbed blood flow; smooth muscle myosin heavy chain; smooth muscle ␣-actin ATHEROSCLEROSIS IS A COMPLEX disease characterized by the accumulation of lipid and cholesterol deposits within the walls of blood vessels, as well as intimal proliferation and extracellular matrix deposition by phenotypically modulated smooth muscle (SM) cells (SMCs) (1). SMCs within human atherosclerotic lesions and experimental atherosclerosis exhibit a distinct morphological change compared with medial SMCs within the normal vessel wall (32). Along with this morphological change, phenotypically modulated SMCs exhibit decreased expression of a variety of contractile genes, including SM ␣-actin, SM myosin heavy chain (MHC), SM22␣, smoothelin, and h1-calponin (32). Advanced atherosclerotic lesions are characterized by a large lipid and necrotic core covered by a fibrous cap, and the thickness and mechanical properties of these lesions are key determinants of the probability of plaque rupture (3, 12, 13), thrombosis, and subsequent acute myocardial infarction or stroke, the leading causes of death in developed countries (3,12,13). Although the precise factors and mechanisms that con...

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Section: Discussionmentioning

confidence: 99%

PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns

Thomas

Deaton²,

Hastings³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Blocking murine/human chimeric antibodies to PDGFR␣ were from Celltech. 28 All other antibodies were purchased from Santa Cruz Biotechnology. [ …”

Section: Methodsmentioning

confidence: 99%

Interleukin-1β Inhibits Expression of p21(WAF1/CIP1) and p27(KIP1) and Enhances Proliferation in Response to Platelet-Derived Growth Factor-BB in Smooth Muscle Cells

Nathe

Deou

Walsh

et al. 2002

ATVB

Self Cite

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Objective-Intimal growth depends on smooth muscle cell (SMC) migration and proliferation and is regulated by thrombotic and inflammatory responses to vascular injury. Platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1␤ have been shown to contribute to intimal hyperplasia and lesion progression in atherosclerosis. Mitogenic effects of IL-1 on SMCs have been reported and have been attributed to the expression of PDGF-A chain. In some, but not all, studies, IL-1␤ was found to cooperate with growth factors, including PDGF, in stimulating proliferation. The molecular basis for such cooperative effects is unknown and is the subject of the present study. Methods and Results-We demonstrate that in baboon aortic SMCs, IL-1␤ enhances the proliferation induced by PDGF-BB independently of PDGF-A signaling. IL-1␤ increases the phosphorylation of retinoblastoma protein, a pivotal step in the G 1 -to-S transition in the cell cycle. Analysis of expression levels of cyclins and cyclin-dependent kinase (CDK) inhibitors suggests that IL-1␤ stimulates CDKs by downregulating p21 and p27. Consistent with this hypothesis is the finding that CDK2 activity, induced by PDGF-BB, is enhanced 2.3Ϯ0.2-fold in the presence of IL-1␤. Key Words: smooth muscle Ⅲ platelet-derived growth factor Ⅲ interleukin-1 Ⅲ p21(WAF1/CIP1) Ⅲ p27(KIP1) Conclusions-Our

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“…There are two PDGF receptors, PDGFR-␣ and PDGFR-␤, whose intrinsic tyrosine kinase activity is activated by PDGF-A alone, or PDGF-A and PDGF-B, respectively (36). The role of PDGF receptors has been described in several postinjury models (46), and it is reported that both PDGF chains and their receptors are detected in human coronary arteries following balloon angioplasty (249,256). Conventional knockout of PDGF-A (20), PDGF-B (141), PDGFR-␣ (241), and PDGFR-␤ (240) has been shown to result in early embryonic or perinatal lethality, thereby prohibiting use of these mice to investigate the role of PDGF signaling in vascular injury responses or experimental atherogenesis.…”

Section: Pdgfmentioning

confidence: 99%

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

Owens

Kumar²,

Wamhoff³

2004

Physiological Reviews

2,930

3,134

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The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

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Effect of Platelet-Derived Growth Factor Receptor-α and -β Blockade on Flow-Induced Neointimal Formation in Endothelialized Baboon Vascular Grafts

Cited by 40 publications

References 43 publications

PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns

PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns

Interleukin-1β Inhibits Expression of p21(WAF1/CIP1) and p27(KIP1) and Enhances Proliferation in Response to Platelet-Derived Growth Factor-BB in Smooth Muscle Cells

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

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