PlGF knockout delays brain vessel growth and maturation upon systemic hypoxic challenge

J Cereb Blood Flow Metab. 2012 Apr;32(4):663-75. doi: 10.1038/jcbfm.2011.167. Epub 2011 Nov 30.


In this study, we have investigated the potential role of placental growth factor (PlGF) in hypoxia-induced brain angiogenesis. To this end, PlGF wild-type (PlGF(+/+)) and PlGF knockout (PlGF(-/-)) mice were exposed to whole body hypoxia (10% oxygen) for 7, 14, and 21 days. PlGF(+/+) animals exhibited a significant ~40% increase in angiogenesis after 7 days of hypoxia compared with controls, while in PlGF(-/-) this effect only occurred after 14 days of hypoxia. No differences in pericyte/smooth muscle cell (SMC) coverage between the two genotypes were observed. After 14 days of hypoxia, PlGF(-/-) microvessels had a significant increase in fibrinogen accumulation and extravasation compared with those of PlGF(+/+), which correlated with endothelial cell disruption of the tight junction protein claudin-5. These vessels displayed large lumens, were surrounded by reactive astrocytes, lacked both pericyte/SMC coverage and endothelial vascular endothelial growth factor expression, and regressed after 21 days of hypoxia. Vascular endothelial growth factor expression levels were found to be significantly lower in the frontal cortex of PlGF(-/-) compared with those in PlGF(+/+) animals during the first 5 days of hypoxia, which in combination with the lack of PlGF may have contributed to the delayed angiogenic response and the prothrombotic phenotype observed in the PlGF(-/-)animals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain* / blood supply
  • Brain* / metabolism
  • Brain* / pathology
  • Brain* / physiopathology
  • Cerebrovascular Circulation*
  • Claudin-5
  • Claudins / biosynthesis
  • Claudins / genetics
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Gene Expression Regulation / genetics
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Hypoxia / physiopathology*
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Proteins / genetics
  • Proteins / metabolism*
  • Tight Junctions / metabolism
  • Tight Junctions / pathology
  • Time Factors
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics


  • Claudin-5
  • Claudins
  • Cldn5 protein, mouse
  • Membrane Proteins
  • Pigf protein, mouse
  • Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse