uPA impairs cerebrovasodilation after hypoxia/ischemia through LRP and ERK MAPK.
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.
Armstead
William M
WM
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA. armsteaw@uphs.upenn.edu
Cines
Douglas B
DB
Bdeir
Khalil
K
Kulikovskaya
Irina
I
Stein
Sherman C
SC
Higazi
Abd Al-Roof
AA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006935:Hypercapnia / Q000378:metabolism / Q000503:physiopathology; D007022:Hypotension / Q000378:metabolism / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034421:Sus scrofa; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D000906:Antibodies; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator