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uPA contributes to impairment of hypercapnic and hypotensive cerebrovasodilation in an LRP and ERK MAPK dependent process
Author(s) -
Armstead William M.,
Cines Douglas B,
Bdeir Khalil,
Higazi Abd AR
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a293-b
Subject(s) - mapk/erk pathway , endocrinology , medicine , antagonist , protein kinase a , receptor , chemistry , kinase , hypercapnia , biology , biochemistry , respiratory system
Cerebral hypoxia/ischemia (H/I) impairs pial artery dilation (PAD) to hypercapnia and hypotension but not isoproterenol in the newborn pig. We investigated the role of endogenous urokinase plasminogen activator (uPA), the low‐density lipoprotein related protein (LRP) receptor, and the ERK isoform of mitogen activated protein kinase (MAPK) in vasodilator impairment 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 4h after H/I, respectively. The LRP antagonist receptor associated protein (RAP) and anti‐LRP antibody blunted the increase in CSF uPA at 1h (17 ± 2 ng/ml) but not 4h post insult. uPA detectable in sham‐treated piglet parietal cortex by immunocytochemistry was markedly elevated 4h after H/I. Phosphorylation (activation) of ERK MAPK was detected 1 and 4h post H/I and blocked by RAP. Exogenous uPA administered at 4h post H/I further stimulated ERK MAPK phosphorylation, blocked by RAP. Pre‐treatment with RAP, anti‐LRP, and soluble uPA receptor completely prevented and the ERK MAPK antagonist U 0126, partially prevented the impairment to hypotension and hypercapnia post‐H/I, but none of these antagonists affected the response to isoproterenol. These data indicate that uPA is released after H/I through an LRP‐initiated process and that the released uPA impairs hypercapnic and hypotensive PAD in an LRP‐ and ERK MAPK‐dependent pathway. These data suggest that modulation of uPA expression and/or action may preserve cerebrohemodynamic control after H/I.