Phenotypical differences in connective tissue cells emerging from microvascular pericytes in response to overexpression of PDGF-B and TGF-β1 in normal skin in vivo

Abstract

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)-β1, 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-β1 could initiate but neither could sustain angiogenesis. Instead, vascular regression was observed. Overexpression of both TGF-β1 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-β1, 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-β1 induced expansion of connective tissue cells with a myofibroblast phenotype, whereas PDGF-B induced a fibroblast phenotype negative for α-smooth muscle actin. TGF-β1 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-β1 on the vasculature and connective tissue in vivo.