title: 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.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Tomas
authors.initials: T
authors.lastname: Friman
authors.forename: Marcin
authors.initials: M
authors.lastname: Kowanetz
authors.forename: Tijs
authors.initials: T
authors.lastname: van Wieringen
authors.forename: Renata
authors.initials: R
authors.lastname: Gustafsson
authors.forename: Christian
authors.initials: C
authors.lastname: Sundberg
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003239:Connective Tissue Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000071235:Fibromodulin; D005786:Gene Expression Regulation / Q000502:physiology; D005822:Genetic Vectors; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000502:physiology; D020286:Pericytes / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; C000604332:Fmod protein, mouse; D011509:Proteoglycans; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D000071235:Fibromodulin