Abstract WMP67: Plasminogen Deficiency And Gender Dimorphism After Thromboembolic Stroke
Background: Stroke is a sex dimorphic disease with males and post-menopausal females having worse outcomes. Plasminogen (Pg) system plays a major role in post-stroke outcomes, affecting clot lysis and MMP-9 regulation. Activation of MMP-9 occurs by both Pg-dependent and Pg-independent mechanisms. However, the role of Pg-dependent molecular pathways in stroke remains unclear. The aim of this work was to determine if there is a sex-specific change in post-stroke neurologic outcomes in mice with Pg deficiency.
Methods: Pg knockout (Pg-/-) and wild type (Pg+/+) mice of both sexes (n=8-14 animals/group; 26±4 weeks old) were subjected to embolic stroke. At 24 hours, behavioral evaluation, infarct area and edema volume were assessed.
Results: Plasminogen deficiency caused pathological fibrin deposition in the microcirculation, inducing a similar systemic inflammatory response in males and females with significantly increased levels of monocytes (1.7-fold, p<0.01) and granulocytes (3.5-fold, p<0.001) in the circulation compared with Pg+/+ mice. Moreover, all pro-thrombotic Pg-/- mice had microcytic anemia due to low red blood cell volume (36.7 fl vs. 41.6 fl, p<0.001). Pg-/- females had lower estrogen levels compared with Pg+/+ females (10.2±12.6 pg/ml vs. 31.5±51 pg/ml; p=0.23). Pg deficiency did not affect the level of MMP-9 in the brain nor in the circulation. Despite the similar levels of systemic pro-thrombotic inflammation in Pg-/- mice of both sexes, we observed a significant gender disparity in stroke outcomes. Pg deficiency in males improved behavioral outcomes (1.6 vs. 3.2; p<0.001), reduced infarct size (32.8% vs. 43.1%; p<0.05) and edema volume (5.7% vs. 15.4%; p<0.001) compared with Pg-/- mice. On the other hand, Pg-/- females had a higher mortality (60% vs. 18%) and a poorer neurologic score (4.6 versus 2.3; p<0.001) due to severe brain injury with an increased volume of infarct (64.8% vs. 19.9%; p<0.001) and edema (13.3% vs. 5.6%; p<0.05) compared with Pg+/+ females.
Conclusion: Unlike males, Pg-/- females had disproportionately poor outcomes compared with Pg+/+ females. Our data demonstrates that Pg-/- female mice may represent an experimental model that mimics females in an early menopausal stage with chronic pro-thrombotic disease.
- © 2012 by American Heart Association, Inc.