Differential actions of VEGF-A isoforms on perichondrial angiogenesis during endochondral bone formation

Dev Biol. 2009 Aug 15;332(2):196-211. doi: 10.1016/j.ydbio.2009.05.552. Epub 2009 May 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone and Bones / drug effects
  • Bone and Bones / physiology
  • Cartilage / drug effects
  • Cartilage / physiology
  • Chick Embryo
  • Chondrocytes / cytology
  • Chondrocytes / drug effects
  • Chondrocytes / physiology
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Embryo, Mammalian / anatomy & histology
  • Embryo, Mammalian / physiology
  • Embryo, Nonmammalian / anatomy & histology
  • Embryo, Nonmammalian / physiology
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Heparan Sulfate Proteoglycans / chemistry
  • Heparan Sulfate Proteoglycans / genetics
  • Heparan Sulfate Proteoglycans / metabolism
  • Humans
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Neovascularization, Physiologic* / drug effects
  • Neovascularization, Physiologic* / physiology
  • Osteoblasts / cytology
  • Osteoblasts / physiology
  • Osteogenesis* / drug effects
  • Osteogenesis* / physiology
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / pharmacology*
  • Transforming Growth Factor beta / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / pharmacology*

Substances

  • Collagen Type I
  • Heparan Sulfate Proteoglycans
  • Peptides
  • Protein Isoforms
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 9