Submitted on October 29, 2008
Revised on January 5, 2009
Accepted on January 20, 2009
Inhibition of Integrin 
V
3 Prevents Urokinase Plasminogen Activator -Mediated Impairment of Cerebrovasodilation After Cerebral Hypoxia/Ischemia
J Willis Kiessling1, Douglas B. Cines1, Abd Al-Roof Higazi, and William M. Armstead1*
1 University of Pennsylvania
* To whom correspondence should be addressed. E-mail: armsteaw{at}uphs.upenn.edu.
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, while blockade of endogenous uPA-mediated vasoactivity prevents it completely. This study investigated the role of integrin 
V
3, in uPA-mediated impairment of cerebrovasodilation after H/I in piglets equipped with a closed cranial window. Pial artery dilation induced by hypercapnia (pCO2 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 V3 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-V3 antibody, respectively). Responses to isoproterenol were unchanged after H/I and combined uPA and anti V3 antibody. Similar results were obtained for combined administration of uPA with the V3 antagonist cRGDfV and RGDS, but not for the inactive analogue, RGDES. These data show that activation of the integrin V3 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.
