Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit

Blood. 2007 Apr 15;109(8):3270-8. doi: 10.1182/blood-2006-08-043125. Epub 2006 Dec 14.

Abstract

The low-density lipoprotein receptor-related protein (LRP) is a member of the LDL receptor gene family that binds several ligands, including tissue-type plasminogen activator (tPA). tPA is found in blood, where its primary function is as a thrombolytic enzyme, and in the central nervous system where it mediates events associated with cell death. Cerebral ischemia induces changes in the neurovascular unit (NVU) that result in brain edema. We investigated whether the interaction between tPA and LRP plays a role in the regulation of the permeability of the NVU during cerebral ischemia. We found that the ischemic insult induces shedding of LRP's ectodomain from perivascular astrocytes into the basement membrane. This event associates with the detachment of astrocytic end-feet processes and the formation of areas of perivascular edema. The shedding of LRP's ectodomain is significantly decreased in tPA deficient (tPA(-/-)) mice, is increased by incubation with tPA, and is inhibited by the receptor-associated protein (RAP). Furthermore, treatment with either RAP or anti-LRP IgG results in a faster recovery of motor activity and protection of the integrity of the NVU following middle cerebral artery occlusion (MCAO). Together, these results implicate tPA/LRP interactions as key regulators of the integrity of the NVU.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Brain Edema / genetics
  • Brain Edema / metabolism*
  • Brain Edema / pathology
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Central Nervous System / blood supply
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • LDL-Receptor Related Protein-Associated Protein / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Permeability
  • Protein Structure, Tertiary / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Plasminogen Activator / deficiency
  • Tissue Plasminogen Activator / metabolism*

Substances

  • LDL-Receptor Related Protein-Associated Protein
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Tissue Plasminogen Activator