title: Differential actions of VEGF-A isoforms on perichondrial angiogenesis during endochondral bone formation.
abstract: During endochondral bone formation, vascular invasion initiates the replacement of avascular cartilage by bone. We demonstrate herein that the cartilage-specific overexpression of VEGF-A(164) in mice results in the hypervascularization of soft connective tissues away from cartilage. Unexpectedly, perichondrial tissue remained avascular in addition to cartilage. Hypervascularization of tissues similarly occurred when various VEGF-A isoforms were overexpressed in the chick forelimb, but also in this case perichondrial tissue and cartilage were completely devoid of vasculature. However, following bony collar formation, anti-angiogenic properties in perichondrial tissue were lost and perichondrial angiogenesis was accelerated by VEGF-A(146), VEGF-A(166), or VEGF-A(190). Once the perichondrium was vascularized, osteoclast precursors were recruited from the circulation and the induction of MMP9 and MMP13 can be observed in parallel with the activation of TGF-beta signaling. Neither perichondrial angiogenesis nor the subsequent cartilage vascularization was found to be accelerated by the non-heparin-binding VEGF-A(122) or by the VEGF-A(166)DeltaE(162)-R(166) mutant lacking a neuropilin-binding motif. Hence, perichondrial angiogenesis is a prerequisite for subsequent cartilage vascularization and is differentially regulated by VEGF-A isoforms.
authors.affiliation: Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Takimoto
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Nishizaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiraki
authors.forename: Chisa
authors.initials: C
authors.lastname: Shukunami
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000502:physiology; D002356:Cartilage / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004625:Embryo, Nonmammalian / Q000033:anatomy & histology / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology*
chemical_list: D024042:Collagen Type I; D019812:Heparan Sulfate Proteoglycans; D010455:Peptides; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9