Urokinase plasminogen activator impairs SNP and PGE2 cerebrovasodilation after brain injury through activation of LRP and ERK MAPK.
Pial artery dilation in response to prostaglandin (PG)E(2) and the nitric oxide (NO) releaser sodium nitroprusside (SNP) are blunted after fluid percussion brain injury (FPI), whereas responses to papaverine are unchanged. Urokinase plasminogen activator (uPA) and ERK mitogen-activated protein kinase (MAPK) are upregulated and contribute to the impairment of cerebrohemodynamics seen after FPI. PA vascular activity is mediated through the low-density lipoprotein receptor (LRP). Therefore, we investigated the role of uPA, LRP, and ERK MAPK in the impaired cerebrovasodilation response to PGE(2) and SNP after FPI. Lateral FPI (2 atm) was induced in anesthetized piglets equipped with a closed cranial window. Cerebrospinal fluid (CSF) ERK MAPK was quantified by enzyme-linked immunosorbent assay (ELISA). Pretreatment with soluble uPA receptor (suPAR), which antagonizes the vascular action of uPA, blunted the impairment of SNP and PGE(2)-mediated dilation seen after FPI. Pretreatment with the LRP antagonist RAP, a monoclonal antibody against LRP (Mab ag LRP) and the ERK MAPK antagonist, U 0126, all provided similar protection, whereas control immunoglobulin G (IgG) had no effect. Responses to papaverine were unchanged after FPI. Upregulation of ERK MAPK phosphorylation in CSF after FPI was blunted in animals pretreated with suPAR, RAP, MAb ag LRP, or U 0126, whereas control IgG had no effect. These data indicate that uPA contributes to the impairment of SNP and PGE(2)-mediated cerebrovasodilation seen after brain injury through activation of LRP and ERK MAPK.
Armstead
William M
WM
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. armsteaw@uphs.upenn.edu
Christine
Amy J
AJ
Higazi
Abd Al-Roof
AA
Cines
Douglas B
DB
D000818:Animals; D000831:Animals, Newborn; D002536:Cerebral Arteries / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D010208:Papaverine / Q000494:pharmacology; D010960:Plasminogen Activators / Q000494:pharmacology*; D013552:Swine; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D010208:Papaverine; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D008071:Lipoprotein Lipase; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D015232:Dinoprostone