title: Inhibition of integrin alphavbeta3 prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia.
abstract: Cerebral hypoxia (10 min) followed immediately by ischemia (20 min) (H/I) impairs cerebrovasodilation in response to hypercapnia and hypotension in the newborn pig; exogenous urokinase plasminogen activator (uPA) potentiates this effect, whereas the blockade of endogenous uPA-mediated vasoactivity prevents it completely. This study investigated the role of integrin alpha(V)beta(3) in the uPA-mediated impairment of cerebrovasodilation after H/I in piglets equipped with a closed cranial window. Pial artery dilation induced by hypercapnia (Pco(2), 75 mmHg) and hypotension (mean arterial blood pressure, decreased by 45%) was blunted after H/I, reversed to vasconstriction in piglets treated with uPA (10(-7) M), a concentration observed in cerebrospinal fluid after H/I, but reverted to a dilation no different than preinsult in piglets administered an anti-alpha(V)beta(3) antibody (10 ng/ml) in addition to uPA (26 +/- 1, 9 +/- 1, -10 +/- 3, and 22 +/- 3% for hypercapnia before H/I, after H/I, after H/I with uPA, and after H/I with combined uPA and anti-alpha(V)beta(3) antibody, respectively). Responses to isoproterenol were unchanged after H/I and combined uPA and anti-alpha(V)beta(3) antibody. Similar results were obtained for the combined administration of uPA with the alpha(V)beta(3) antagonist Arg-Gly-Asp-d-Phe-Val and Arg-Gly-Asp-Ser, but not for the inactive analog Arg-Gly-Asp-Glu-Ser acetate. These data show that the activation of the integrin alpha(V)beta(3) contributes to the uPA-mediated impairment of pial artery dilation after H/I. These data suggest that the inhibition of uPA and integrin signaling may preserve cerebrohemodynamic control after H/I.
authors.affiliation: Dept. of Anesthesiology and Critical Care, 3620 Hamilton Walk, JM3, Univ. of Pennsylvania, Philadelphia, PA l9l04, USA.
authors.forename: J Willis
authors.initials: JW
authors.lastname: Kiessling
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006935:Hypercapnia / Q000201:enzymology / Q000503:physiopathology; D007022:Hypotension / Q000201:enzymology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000503:physiopathology; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D000906:Antibodies; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; C046617:arginyl-glycyl-aspartyl-serine; D014568:Urokinase-Type Plasminogen Activator; D007545:Isoproterenol