Blockade of Platelet-Derived Growth Factor or Its Receptors Transiently Delays but Does Not Prevent Fibrous Cap Formation in ApoE Null Mice

Kozaki, Koichi; Kaminski, Wolfgang E.; Tang, Jingjing; Hollenbach, Stan; Lindahl, Per; Sullivan, Carol M.; Yu, Jin Chen; Abe, Keith; Martin, Paul J.; Ross, Russell; Betsholtz, Christer; Giese, Neill A.; Raines, Elaine W.

doi:10.1016/s0002-9440(10)64415-x

Cited by 79 publications

(76 citation statements)

References 69 publications

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“…In cultured SMCs, PDGF-BB represses expression of multiple SMC differentiation marker genes and coordinately increases SMC proliferation, migration, and matrix synthesis, consistent with SMC phenotypic modulation to a synthetic state (2,4,7,26,34). In addition, in vivo blockade of PDGF-BB or PDGFR-␤ reduces SMC migration into neointimal lesions after vascular injury and decreases SMC accumulation and fibrous cap formation within developing atherosclerotic plaques in mice (25,37,54,66,69). Recent studies have demonstrated that PDGF-DD, a newly discovered PDGF isoform that is a more selective agonist of the PDGFR-␤, also promotes SMC phenotypic modulation through repressing SMC differentiation marker gene expression and increasing SMC proliferation and migration (5,13,38,73).…”

mentioning

confidence: 70%

“…Indeed, as opposed to our observation of overrepresentation of NF-B binding sites in distinctly IL-1-induced genes, genes distinctly induced by PDGF-DD exhibited overrepresentation of binding sites for E2F family members (Table 5), which are known regulators of cell proliferation (3,24). As such, it is interesting to postulate that it may be feasible to therapeutically target NF-B to selectively inhibit transition of SMC to an inflammatory state while retaining a PDGF-induced proliferative SMC phenotype that may contribute to plaque stabilization through enhancing SMC accumulation within plaques and formation of a protective fibrous cap (37,66).…”

Section: Discussionmentioning

confidence: 99%

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Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms

Alexander

Murgai

Moehle

et al. 2012

Physiological Genomics

105

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mentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms

Alexander

Murgai

Moehle

et al. 2012

Physiological Genomics

105

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“…Restenosis following angioplasty of atherosclerotic vessels in minipigs (Bilder et al 1999) and chronic cardiac transplant rejection-induced atherosclerosis in rats (Sihvola et al 1999) were also inhibited by PDGFR-blocking kinase inhibitors. In ApoE-deficient mice, atherosclerotic lesions were inhibited by neutralizing PDGFR-␤ antibodies (Sano et al 2001) and a PDGFR blocking kinase inhibitor (Kozaki et al 2002). Conversely, infusion of PDGF-BB (Jawien et al 1992) or local transfection of a PDGF-B expression vector (Nabel et al 1993) led to increased SMC proliferation and intima thickening in certain models of arterial injury.…”

Section: Atherosclerosis and Restenosismentioning

confidence: 99%

“…This suggests impaired migration of vSMC from the media to the intima in the absence of functional PDGFR-␤ (Buetow et al 2003). Another type of chimeric situation was obtained by bone marrow transplantations of PDGF-B-deficient marrow into lethally irradiated, ApoE-deficient recipients (Kozaki et al 2002). The lack of PDGF-B production by infiltrating inflammatory cells led to a small and transient inhibition of neointimal fibrous cap formation.…”

Section: Platelet-derived Growth Factor Genes and Development 1295mentioning

confidence: 99%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

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2,075

1,898

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-␣ signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-␤ signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.Platelet-derived growth factor (PDGF) was identified more than three decades ago as a serum growth factor for fibroblasts, smooth muscle cells (SMCs), and glia cells (Kohler and Lipton 1974;Ross et al. 1974;Westermark and Wasteson 1976). Human PDGF was originally identified as a disulfide-linked dimer of two different polypeptide chains, A and B, separable using reversed phase chromatography (Johnsson et al. 1982). The B-chain (PDGF-B) was characterized by amino acid sequencing, revealing a close homology between PDGF-B and the product of the retroviral oncogene v-sis of simian sarcoma virus (SSV) (Doolittle et al. 1983;Waterfield et al. 1983). Subsequent studies confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B and that autocrine PDGF activity was sufficient for SSV transformation in vitro. This was a paradigm-shifting discovery about the relationship between neoplastic cell transformation and normal growth control. For the first time, the importance of autocrine growth stimulation in neoplastic transformation was demonstrated. As discussed below, it is now well established that autocrine PDGF stimulation plays a role also in some human cancers.PDGF-A was characterized by cDNA cloning ). This resolved a paradoxical lack of correlation between secretion of PDGF-like growth factors from tumor cell lines and their expression of c-sis; it turned out that most such cell lines express PDGF-A and secrete PDGF-AA homodimers ). Together with the demonstration that PDGF-BB homodimers are produced by SSV-transformed or PDGF-Bexpressing cells, these results showed that the PDGF...

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“…PDGFR ligation is generally pro-proliferative and antiapoptotic (in part through PKB and ERK activation) as well as anti-inflammatory and profibrotic. In one study, transplant of PDGF-B-null fetal liver cells into irradiated ApoE Ϫ/Ϫ mice resulted only in a delay of VSMC accumulation and fibrous cap formation without a change in lesion volume (945). In addition, macrophages appeared more inflammed or activated in the PDGF-B-null chimeric mice.…”

Section: Newer Insights Into the Role Of Vsmc In Atherosclerosismentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

390

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Blockade of Platelet-Derived Growth Factor or Its Receptors Transiently Delays but Does Not Prevent Fibrous Cap Formation in ApoE Null Mice

Abstract: Platelet-derived growth factor (PDGF) is

Cited by 79 publications

References 69 publications

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms

Role of platelet-derived growth factors in physiology and medicine

Molecular Biology of Atherosclerosis

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