Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1–derived (PGHS1-derived) thromboxane A2 (TxA2) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1Neo/Neo) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA2 by 98% in PGHS1Neo/Neo mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE2 by 75% was associated with selectively impaired inflammatory responses. PGF2α at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1Neo/Neo mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1Neo/Neo mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function.
Ying Yu, Yan Cheng, Jinjin Fan, Xin-Sheng Chen, Andres Klein-Szanto, Garret A. FitzGerald, Colin D. Funk
Title and authors | Publication | Year |
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Cyclooxygenases, mPGE Synthase-1 and Cardiovascular Function
Yan Cheng, Miao Wang, Ying Yu, John Lawson, Colin D. Funk, Garret A. FitzGerald |
Journal of Clinical Investigation | 2006 |
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities
T Grosser, S Fries, GA FitzGerald |
Journal of Clinical Investigation | 2006 |
Differential compensation of two cyclooxygenases in renal homeostasis is independent of prostaglandin-synthetic capacity under basal conditions
X Li, LL Mazaleuskaya, LL Ballantyne, H Meng, GA FitzGerald, CD Funk |
The FASEB Journal | 2006 |