Expression of platelet-derived growth factor isoforms and their receptors in cells accumulating in the human atherosclerotic lesion
Atherosclerosis is a progressive and complex disease, which narrows the lumen of arteries and eventually causes cardiovascular complications such as ischaemic heart disease and stroke. Hallmarks of the disease development are; a compromised endothelial barrier, the accumulation of lipids and immunocompetent monocyte-derived macrophages (MDM) and T-cells, the formation of MDM foam cells, and migration and proliferation of medial arterial smooth muscle cells (SMC) in the innermost layer (intima) of the arterial wall. While lipid-lowering therapy favourably retards atherosclerosis progression by reducing the lipid component of intimal thickenings, there is no effective therapy to control cell accumulation in the intima. A key role in this cellular response has been attributed to the Platelet-Derived Growth Factor (PDGF). The main aims of this thesis were to establish a better understanding of the role of PDGF and its receptors (PDGF-R) in the cellular responses in the complex atherosclerotic plaque by studying human SMC and MDM in simplified in vitro systems. Specifically, I studied i) if the expressions of PDGF isoforms and their receptors are affected by changes in cell phenotype, ii) if this expression is modulated by exogenous cytokines, and iii) if different PDGF homodimers affect major cellular events in the atherosclerotic lesion; proliferation of SMC and migration of MDM. The results showed that human SMC and MDM expressed PDGF and PDGF-Rs in vitro. Both PDGF and PDGF-R genes were independently regulated and showed a complex gene regulatory pattern. The expression of these genes could be influenced by phenotypic changes and cytokines. SMC downregulated PDGF mRNA during dedifferentiation upon serum exposure. In contrast, blood-derived monocytes differentiated to MDM in the presence of serum and increased both PDGF isoform mRNAs, suggesting that PDGF might be important during macrophage differentiation. All tested PDGF homodimers (PDGF-AAL, -AAS, and -BBS) induced SMC proliferation whereas only PDGF-AAL induced directed migration in early MDM and this was coupled to an increase in PDGF-Ra expression. Taken together, these results suggest that PDGF-mediated mechanisms may be involved in cell accumulation in atherosclerotic lesions, influencing proliferation of SMC and chemoattraction of early MDM.
Parts of work
Quantitation of platelet-derived growth factor receptors in human arterial smooth muscle cells in vitro. Krettek A, Fager G, Jernberg P, Ostergren-Lundén G, Lustig F. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2395-404. ::PMID::9409207Effect of phenotype on the transcription of the genes for platelet-derived growth factor (PDGF) isoforms in human smooth muscle cells, monocyte-derived macrophages, and endothelial cells in vitro. Krettek A, Fager G, Lindmark H, Simonson C, Lustig F. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2897-903. ::PMID::9409273Expression of PDGF receptors and ligand-induced migration of partially differentiated human monocyte-derived macrophages. Influence of IFN-gamma and TGF-beta. Krettek A, Ostergren-Lundén G, Fager G, Rosmond C, Bondjers G, Lustig F. Atherosclerosis. 2001 Jun;156(2):267-75 ::PMID::11395022
Göteborgs universitet/University of Gothenburg
Department of Cardiovascular Prevention
Avdelningen för kardiovaskulär prevention
Date of defence