title: Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival.
abstract: VEGF is crucial for metaphyseal bone vascularization. In contrast, the angiogenic factors required for vascularization of epiphyseal cartilage are unknown, although this represents a developmentally and clinically important aspect of bone growth. The VEGF gene is alternatively transcribed into VEGF(120), VEGF(164), and VEGF(188) isoforms that differ in matrix association and receptor binding. Their role in bone development was studied in mice expressing single isoforms. Here we report that expression of only VEGF(164) or only VEGF(188) (in VEGF(188/188) mice) was sufficient for metaphyseal development. VEGF(188/188) mice, however, showed dwarfism, disrupted development of growth plates and secondary ossification centers, and knee joint dysplasia. This phenotype was at least partly due to impaired vascularization surrounding the epiphysis, resulting in ectopically increased hypoxia and massive chondrocyte apoptosis in the interior of the epiphyseal cartilage. In addition to the vascular defect, we provide in vitro evidence that the VEGF(188) isoform alone is also insufficient to regulate chondrocyte proliferation and survival responses to hypoxia. Consistent herewith, chondrocytes in or close to the hypoxic zone in VEGF(188/188) mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF(188) isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation.
authors.affiliation: Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Christa
authors.initials: C
authors.lastname: Maes
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stockmans
authors.forename: Karen
authors.initials: K
authors.lastname: Moermans
authors.forename: Riet
authors.initials: R
authors.lastname: Van Looveren
authors.forename: Nico
authors.initials: N
authors.lastname: Smets
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
mesh_terms: D000792:Angiography; D000818:Animals; D001846:Bone Development; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002356:Cartilage / Q000166:cytology / Q000473:pathology; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004838:Epiphyses / Q000098:blood supply* / Q000378:metabolism*; D000860:Hypoxia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008954:Models, Biological; D016296:Mutagenesis; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D011995:Recombination, Genetic; D012261:Ribonucleoproteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry* / Q000235:genetics*; D029867:Xenopus Proteins
chemical_list: D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D042461:Vascular Endothelial Growth Factor A; D029867:Xenopus Proteins; C068598:Msi1 protein, Xenopus; D040262:Receptors, Vascular Endothelial Growth Factor; D001973:Bromodeoxyuridine