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: J Willis Kiessling, Douglas B Cines, Abd Al-Roof Higazi, William M Armstead
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 296 Issue 3 Pg. H862-7 (Mar 2009) ISSN: 0363-6135 [Print] United States
• PMID: 19168722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• Antibodies
• Integrin alphaVbeta3
• Oligopeptides
• Peptides
• Peptides, Cyclic
• arginyl-glycyl-aspartyl-serine
• Urokinase-Type Plasminogen Activator
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Animals, Newborn
• Antibodies (pharmacology)
• Cerebrovascular Circulation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Hypercapnia (enzymology, physiopathology)
• Hypotension (enzymology, physiopathology)
• Hypoxia-Ischemia, Brain (enzymology, physiopathology)
• Integrin alphaVbeta3 (antagonists & inhibitors, metabolism)
• Isoproterenol (pharmacology)
• Male
• Oligopeptides (pharmacology)
• Peptides (pharmacology)
• Peptides, Cyclic (pharmacology)
• Signal Transduction (drug effects)
• Swine
• Urokinase-Type Plasminogen Activator (administration & dosage, metabolism)
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)