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Inhibition of integrin aVB3 prevents uPA–mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia
Author(s) -
Armstead William M,
Kiessling J Willis,
Cines Douglas B,
Higazi Abd AlRoof
Publication year - 2009
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.23.1_supplement.613.5
Subject(s) - hypercapnia , ischemia , endogeny , integrin , hypoxia (environmental) , endocrinology , chemistry , antagonist , medicine , antibody , receptor , immunology , oxygen , acidosis , organic chemistry
Cerebral hypoxia/ischemia (H/I) impairs cerebrovasodilation in response to hypercapnia and hypotension in the newborn pig, exogenous uPA potentiates this effect, while blockade of endogenous uPA‐mediated vasoactivity prevents it completely. This study investigated the role of integrin α Vβ3 , in 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 mm Hg) 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 CSF after H/I, but reverted to dilation no different than pre‐insult in piglets administered an anti α 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‐α Vβ3 antibody). Responses to isoproterenol were unchanged after H/I and combined uPA and anti α Vβ3 antibody. Similar results were obtained for combined administration of uPA with the α Vβ3 antagonist cRGDfV and RGDS, but not for the inactive analogue, RGDES. These data show that activation of the integrin α Vβ3 contributes to uPA‐ mediated impairment of pial artery dilation after H/I. These data suggest that inhibition of uPA and integrin signaling may preserve cerebrohemodynamic control after H/I.