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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H862    most recent 01141.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kiessling, J. W. Articles by Armstead, W. M. Search for Related Content PubMed PubMed Citation Articles by Kiessling, J. W. Articles by Armstead, W. M.

Inhibition of integrin _Vβ₃ prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia

Departments of ¹Anesthesiology and Critical Care and Pharmacology and ²Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ³Department of Clinical Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel

Submitted 29 October 2008 ; accepted in final form 20 January 2009

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 _Vβ₃ in the uPA-mediated impairment of cerebrovasodilation after H/I in piglets equipped with a closed cranial window. Pial artery dilation induced by hypercapnia (PCO₂, 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-_Vβ₃ 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-_Vβ₃ antibody, respectively). Responses to isoproterenol were unchanged after H/I and combined uPA and anti-_Vβ₃ antibody. Similar results were obtained for the combined administration of uPA with the _Vβ₃ 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 _Vβ₃ 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.

cerebral circulation; newborn; signal transduction