Abstract
Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.
Highlights
Observed in mice in which the gene for the nuclear factor I-C has been knocked out[14]
The decrease in both extra-cellular matrix (ECM)-deposition and angiogenesis, when PDGFRα expression had been largely suppressed in the α -KO fibroblasts, were the most striking phenotypes obtained in the connective tissue growing into the sponge matrices
The expression of PDGFRα and PDGFRβ can be induced in vascular endothelial cells, and has been reported to directly contribute to the blood vessel formation[29,30]
Summary
Observed in mice in which the gene for the nuclear factor I-C has been knocked out[14]. It has been suggested that PDGFRα might contribute to CTR through a different mechanism than that of PDGFRβ. In order to understand the role of PDGFRα in CTR, we established a mouse line (α -KO) in which the Pdgfra gene was ubiquitously inactivated by tamoxifen-induced Cre recombinase. While PDGFRα expression was principally observed in fibroblasts within the ingrowing connective tissues of the sponge matrices implanted in the control mice (Flox mice), it was effectively depleted in the fibroblasts of the α -KO mice. Decreased angiogenesis and ECM deposition were the most striking phenotypes during CTR of the α -KO mice. These phenotypes were different from those obtained after PDGFRβ inhibition[8,10] and suggest a distinctive role for PDGFRα during CTR
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