VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization

Cells. 2019 Nov 6;8(11):1396. doi: 10.3390/cells8111396.


Alternative splicing leads to the secretion of multiple forms of vascular endothelial growth factor-A (VEGF-A) that differ in their activity profiles with respect to neovascularization. FSAP (factor VII activating protease) is the zymogen form of a plasma protease that is activated (FSAPa) upon tissue injury via the release of histones. The purpose of the study was to determine if FSAPa regulates VEGF-A activity in vitro and in vivo. FSAP bound to VEGF165, but not VEGF121, and VEGF165 was cleaved in its neuropilin/proteoglycan binding domain. VEGF165 cleavage did not alter its binding to VEGF receptors but diminished its binding to neuropilin. The stimulatory effects of VEGF165 on endothelial cell proliferation, migration, and signal transduction were not altered by FSAP. Similarly, proliferation of VEGF receptor-expressing BAF3 cells, in response to VEGF165, was not modulated by FSAP. In the mouse matrigel model of angiogenesis, FSAP decreased the ability of VEGF165, basic fibroblast growth factor (bFGF), and their combination, to induce neovascularization. Lack of endogenous FSAP in mice did not influence neovascularization. Thus, FSAP inhibited VEGF165-mediated angiogenesis in the matrigel model in vivo, where VEGF's interaction with the matrix and its diffusion are important.

Keywords: HABP2; VEGF; factor VII activating protease; hind limb ischemia; matrigel; neo-vascularization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Collagen / metabolism
  • Drug Combinations
  • Female
  • Fibroblast Growth Factors / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunophilins / metabolism
  • Laminin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / metabolism*
  • Protein Binding / physiology
  • Proteoglycans / metabolism
  • Serine Endopeptidases / metabolism*
  • Signal Transduction / physiology
  • Vascular Endothelial Growth Factor A / metabolism*


  • Drug Combinations
  • Laminin
  • Proteoglycans
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • matrigel
  • Fibroblast Growth Factors
  • Collagen
  • HABP2 protein, human
  • Serine Endopeptidases
  • Immunophilins