Phenotypical Differences in Connective Tissue Cells Emerging from Microvascular Pericytes in Response to Overexpression of PDGF-B and TGF-@b1 in Normal Skin in Vivo

摘要

Fibrosis is a deleterious consequence of chronic inflammation in a number of human pathologies ultimately leading to organ dysfunction and failure. Two growth factors that are important in blood vessel physiology and tissue fibrosis, platelet-derived growth factor (PDGF)-B and transforming growth factor (TGF)-@b1, were investigated. Adenoviral vectors were used to induce transient overexpression of these growth factors in mouse skin. Changes in tissue structure and protein and mRNA expressions were investigated. Both PDGF-B and TGF-@b1 could initiate but neither could sustain angiogenesis. Instead, vascular regression was observed. Overexpression of both TGF-@b1 and PDGF-B led to a marked macrophage influx and an expansion of the connective tissue cell population. Over time, this effect was sustained in mice treated with TGF-@b1, whereas it was partially reversible in mice treated with PDGF-B. On the basis of structure and expression of phenotypical markers, the emerging connective tissue cell population may originate from microvascular pericytes. TGF-@b1 induced expansion of connective tissue cells with a myofibroblast phenotype, whereas PDGF-B induced a fibroblast phenotype negative for @a-smooth muscle actin. TGF-@b1 and PDGF-B overexpressions mediated distinct effects on mRNA transcript levels of fibrillar procollagens, their modifying enzymes, small leucin-rich repeat proteoglycans, and matricellular proteins affecting both the composition and the quantity of the extracellular matrix. This study offers new insight into the effects of PDGF-B and TGF-@b1 on the vasculature and connective tissue in vivo.