title: Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.
abstract: Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF120 isoform (VEGF120/120 mice). Neonatal VEGF120/120 long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF120/120 bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF120/120 bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF164 and/or VEGF188 is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts.
authors.affiliation: Laboratory of Experimental Medicine and Endocrinology, KU Leuven, B-3000, Leuven, Belgium.
authors.forename: Christa
authors.initials: C
authors.lastname: Maes
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Karen
authors.initials: K
authors.lastname: Moermans
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stockmans
authors.forename: Nico
authors.initials: N
authors.lastname: Smets
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000098:blood supply*; D002356:Cartilage / Q000002:abnormalities / Q000196:embryology; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000473:pathology / Q000502:physiology; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008222:Lymphokines / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008682:Metatarsal Bones / Q000196:embryology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009999:Ossification, Heterotopic; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D020033:Protein Isoforms / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020780:Matrix Metalloproteinase 9