uPA impairs cerebrovasodilation after hypoxia/ischemia through LRP and ERK MAPK.

Abstract

We have previously observed that soluble urokinase plasminogen activator receptor (suPAR) prevents impairment of cerebrovasodilation induced by hypercapnia and hypotension after hypoxia/ischemia (H/I) in the newborn pig. In this study, we investigated the role of low-density lipoprotein-related protein (LRP) receptor and the ERK isoform of mitogen activated protein kinase (MAPK) in uPA-mediated impairment of vasodilation after H/I in piglets equipped with a closed cranial window. CSF uPA increased from 9+/-2 to 52+/-8 and 140+/-21 ng/ml at 1 and 4 h after H/I, respectively. The LRP antagonist receptor associated protein (RAP) and anti-LRP antibody blunted the increase in CSF uPA at 1 h (17+/-2 ng/ml) but not 4 h post insult. uPA detectable in sham-treated cortex by immunohistochemistry was markedly elevated 4 h after H/I. Phosphorylation (activation) of CSF ERK MAPK was detected at 1 and 4 h post H/I and blocked by RAP. Exogenous uPA administered at 4 h post H/I further stimulated ERK MAPK phosphorylation, which was blocked by RAP. Pre-treatment of piglets with RAP, anti-LRP, and suPAR completely prevented, and the ERK MAPK antagonist U 0126 partially prevented, impaired responses to hypotension and hypercapnia post H/I, but none of these antagonists affected the response to isoproterenol. These data indicate that uPA is upregulated after H/I through an LRP-dependent process and that the released uPA impairs hypercapnic and hypotensive dilation through an LRP- and ERK MAPK dependent pathway. These data suggest that modulation of uPA upregulation and/or uPA-mediated signal transduction may preserve cerebrohemodynamic control after hypoxia/ischemia.

• Authors: William M Armstead, Douglas B Cines, Khalil Bdeir, Irina Kulikovskaya, Sherman C Stein, Abd Al-Roof Higazi
• Journal: Brain research (Brain Res) Vol. 1231 Pg. 121-31 (Sep 22 2008) ISSN: 0006-8993 [Print] Netherlands
• PMID: 18656457 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Low Density Lipoprotein Receptor-Related Protein-1
• Mitogen-Activated Protein Kinase 3
• Urokinase-Type Plasminogen Activator

Topics

• Animals
• Antibodies (pharmacology)
• Cerebral Arteries (drug effects, metabolism, physiopathology)
• Female
• Hypercapnia (metabolism, physiopathology)
• Hypotension (metabolism, physiopathology)
• Hypoxia-Ischemia, Brain (drug therapy, metabolism, physiopathology)
• Low Density Lipoprotein Receptor-Related Protein-1 (metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation (drug effects)
• Sus scrofa
• Time Factors
• Up-Regulation (drug effects)
• Urokinase-Type Plasminogen Activator (metabolism, pharmacology)
• Vasodilation (drug effects)