PDGFβ Receptor Blockade Inhibits Intimal Hyperplasia in the Baboon

Hart, Charles E.; Kraiss, Larry W.; Vergel, Selina; Gilbertson, Debra G.; Kenagy, Richard D.; Kirkman, Thomas R.; Crandall, David L.; Tickle, Simon; Finney, Helene; Yarranton, G. T.; Clowes, Alexander W.

doi:10.1161/01.cir.99.4.564

Cited by 103 publications

(77 citation statements)

References 22 publications

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“…4,5 In contrast, blockade of PDGF receptor-␣ (PDGFR␣) has no effect on intimal hyperplasia in that model. 5 The PDGF family consists of 4 peptides, PDGF-A, PDGF-B, and the recently described PDGF-C 6,7 and PDGF-D chains.…”

mentioning

confidence: 77%

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

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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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confidence: 77%

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

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“…A number of different gain-and loss-of-function experiments suggest a role for PDGF in animal models of atherosclerosis. Specifically, in different animal models of acute arterial injury by balloon catheterization, neointimal SMC accumulation was reduced by the administration of various PDGF pathway inhibitors, including neutralizing PDGF (AB) antibodies (Ferns et al 1991;Lewis et al 2001), PDGF-B aptamers (Leppänen et al 2000), PDGFR kinase inhibitors (Banai et al 1998;Yamasaki et al 2001), and PDGFR-neutralizing antibodies (Giese et al 1999;Hart et al 1999). 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.…”

Section: Atherosclerosis and Restenosismentioning

confidence: 99%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

1,990

1,843

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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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“…Thus, enhanced activation of the PDGF signaling pathway is implicated in the development of atherosclerosis, vascular injury-induced restenosis, angiogenesis, and fibrosis (5). A significant contribution of PDGF to vascular remodeling was confirmed by studies demonstrating that neointimal smooth muscle cell accumulation was reduced by administration of either PDGF-B (6) or PDGFR neutralizing antibodies (7,8) during vascular injury induced by balloon catheterization. Conversely, expression of PDGF-B in the vasculature leads to increased SMC proliferation and intima thickening (9).…”

mentioning

confidence: 95%

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Forms a Signaling Complex with Platelet-derived Growth Factor Receptor-β in Endosomes and Regulates Activation of the MAPK Pathway

Muratoglu

Mikhailenko

Newton

et al. 2010

Journal of Biological Chemistry

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In addition to its endocytic function, the low density lipoprotein receptor-related protein 1 (LRP1) also contributes to cell signaling events. In the current study, the potential of LRP1 to modulate the platelet-derived growth factor (PDGF) signaling pathway was investigated. PDGF is a key regulator of cell migration and proliferation and mediates the tyrosine phosphorylation of LRP1 within its cytoplasmic domain. In WI-38 fibroblasts, PDGF-mediated LRP1 tyrosine phosphorylation occurred at 37°C but not at 4°C, where endocytosis is minimized. Furthermore, blockade of endocytosis with the dynamin inhibitor, dynasore, also prevented PDGFmediated LRP1 tyrosine phosphorylation. Immunofluorescence studies revealed co-localization of LRP1 with the PDGF receptor after PDGF treatment within endosomal compartments, whereas surface biotinylation experiments confirmed that phosphorylated LRP1 primarily originates from intracellular compartments. Together, the data reveal the association of these two receptors in endosomal compartments where they form a signaling complex. To study the contribution of LRP1 to PDGF signaling, we used mouse embryonic fibroblasts genetically deficient in LRP1 and identified phenotypic changes in these cell lines in response to PDGF stimulation by performing phospho-site profiling. Of 38 phosphorylated proteins analyzed, 8 were significantly different in LRP1 deficient fibroblasts and were restored when LRP1 was expressed back in these cells. Importantly, the results revealed that LRP1 expression is necessary for PDGF-mediated activation of ERK. Overall, the studies reveal that LRP1 associates with the PDGF receptor in endosomal compartments and modulates its signaling properties affecting the MAPK and Akt/phosphatidylinositol 3-kinase pathways.

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PDGFβ Receptor Blockade Inhibits Intimal Hyperplasia in the Baboon

Abstract: These data suggest that platelet-derived growth factor plays a key role in the development of intimal lesions at sites of acute vascular injury in the nonhuman primate.

Cited by 103 publications

References 22 publications

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

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

Role of platelet-derived growth factors in physiology and medicine

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Forms a Signaling Complex with Platelet-derived Growth Factor Receptor-β in Endosomes and Regulates Activation of the MAPK Pathway

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