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Inhibition of integrin αVβ3 prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia

By J. Willis Kiessling, Douglas B. Cines, Abd Al-Roof Higazi and William M. Armstead


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 αVβ3 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-αVβ3 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-αVβ3 antibody, respectively). Responses to isoproterenol were unchanged after H/I and combined uPA and anti-αVβ3 antibody. Similar results were obtained for the combined administration of uPA with the αVβ3 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 αVβ3 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

Topics: Articles
Publisher: American Physiological Society
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Provided by: PubMed Central
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