Prostate specific membrane antigen produces pro-angiogenic laminin peptides downstream of matrix metalloprotease-2

Angiogenesis. 2013 Oct;16(4):847-60. doi: 10.1007/s10456-013-9360-y. Epub 2013 Jun 18.

Abstract

Prostate specific membrane antigen (PSMA) is a pro-angiogenic cell-surface protease that we previously demonstrated regulates blood vessel formation in a laminin and integrin β1-dependent manner. Here, we examine the principal mechanism of PSMA activation of integrin β1. We show that digesting laminin sequentially with recombinant matrix metalloprotease-2 (MMP-2) and PSMA generates small peptides that enhance endothelial cell adhesion and migration in vitro. We also provide evidence that these laminin peptides activate adhesion via integrin α6β1 and focal adhesion kinase. Using an in vivo Matrigel implant assay, we show that these MMP/PSMA-derived laminin peptides also increase angiogenesis in vivo. Together, our results reveal a novel mechanism of PSMA activation of angiogenesis by processing laminin downstream of MMP-2.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Surface / physiology*
  • Cell Adhesion
  • Cell Movement
  • Collagen / metabolism
  • Drug Combinations
  • Drug Implants
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Female
  • Glutamate Carboxypeptidase II / physiology*
  • Human Umbilical Vein Endothelial Cells
  • Integrin alpha6beta1 / physiology
  • Laminin / administration & dosage
  • Laminin / metabolism*
  • Laminin / pharmacology
  • Matrix Metalloproteinase 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microvessels / growth & development
  • Neovascularization, Physiologic / drug effects*
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / pharmacology
  • Protein Processing, Post-Translational
  • Proteoglycans
  • Recombinant Proteins / metabolism
  • Substrate Specificity

Substances

  • Antigens, Surface
  • Drug Combinations
  • Drug Implants
  • Integrin alpha6beta1
  • Laminin
  • Peptide Fragments
  • Proteoglycans
  • Recombinant Proteins
  • laminin 10
  • matrigel
  • Collagen
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II
  • MMP2 protein, human
  • Matrix Metalloproteinase 2