title: Dual action of TGF-β induces vascular growth in vivo through recruitment of angiogenic VEGF-producing hematopoietic effector cells.
abstract: The role of Transforming growth factor β (TGF-β) as a regulator of blood vessel endothelium is complicated and controversial, and the mechanisms by which TGF-β is able to induce angiogenesis in vivo are not well understood. Here we show that TGF-β causes in vivo a massive recruitment of tissue infiltrating hematopoietic cells. Concurrently, TGF-β induces strong vascular endothelial growth factor (VEGF) production in the recruited hematopoietic cells, resulting in activated angiogenesis and vascular remodeling. TGF-β also promoted abnormalities of α-smooth muscle actin-expressing pericytes on angiogenic capillaries. TGF-β-induced angiogenic effect was inhibited by a systemic treatment with VEGF-neutralizing antibodies. When studied in isolated human hematopoietic cells, physiological concentrations of TGF-β stimulated VEGF mRNA and protein expression in a dose- and time-dependent manner. This induction was p38 and p44/p42 mitogen activated kinase dependent. p38 and p44/p42 activation was also observed in vivo in TGF-β-treated angiogenic murine tissues. Taken together, our results provide a dual action mechanism by which TGF-β promotes angiogenesis in vivo via recruitment of paracrine VEGF-expressing hematopoietic effector cells. This mechanism may activate vascular growth and remodeling during inflammatory conditions and tumor growth when TGF-β activity is upregulated.
authors.affiliation: Department of Pathology and Research Programs, University of Helsinki, POB 63, 00014, Helsinki, Finland.
authors.forename: Shentong
authors.initials: S
authors.lastname: Fang
authors.forename: Nalle
authors.initials: N
authors.lastname: Pentinmikko
authors.forename: Maritta
authors.initials: M
authors.lastname: Ilmonen
authors.forename: Petri
authors.initials: P
authors.lastname: Salven
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D020928:Mitogen-Activated Protein Kinases