Roles of platelet-derived growth factor-C and early growth response-1 in vascular smooth muscle cells
2010
Hochschulschrift
Zugriff:
Smooth muscle cell (SMC) proliferation and migration are key pathophysiological processes regulating vascular remodelling and atherosclerosis. Members of the platelet-derived growth factor (PDGF) family have been identified as participants of such processes. Although the classical PDGF members, PDGF-A and PDGF-B, have been extensively investigated, the newer members, PDGF-C and PDGF-D, are just beginning to be explored. Although the role of PDGF-C in a number of pathophysiological conditions is being investigated, the molecular mechanisms behind its transcriptional activation are yet to be elucidated. The first study in this thesis explored the transcriptional regulation of PDGF-C by Angiotensin II (ATII) in SMCs. So far, no studies have linked ATII with PDGF-C expression. This study demonstrated for the first time that in neonatal SMCs ATII is capable of inducing PDGF-C via signalling through the ATII type 1 receptor (AT1R) and Egr-1. We also identified a novel Egr-1 binding element in the PDGF-C promoter. Not only is PDGF-C up-regulation Egr-1 dependent but intriguingly is SMC subtype-dependent, underlying the heterogeneity of the SMC population. The zinc-finger transcription factor Egr-1 serves as a key regulator of the inducible transcription of many genes implicated in the onset and progression of atherosclerosis. However, understanding of the signalling mechanisms regulating its rapid induction after agonist exposure is poorly understood, beyond the involvement of the RAS/RAF/MEK/ERK or MKK/JNK pathways and serum-response element (SRE)-dependent transcription. In the second study, the mechanisms behind PDGF-BB induction of Egr-1 were examined. In neonatal WKY12-22 SMCs, it was discovered that MMPs/ADAMs and EGFR play essential roles in signalling via PDGF-BB/PDGFRβ/EGFR/ERK1/2/Egr-1. These findings also provide new mechanisms by which PDGFRβ can heterodimerise with EGFR, and emphasises the role of EGFR in PDGFRβ-inducible downstream signaling.
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Roles of platelet-derived growth factor-C and early growth response-1 in vascular smooth muscle cells
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Autor/in / Beteiligte Person: | Sanchez Guerrero, Yanedth Estella |
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Veröffentlichung: | 2010 |
Medientyp: | Hochschulschrift |
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