Differential impact of prostaglandin H synthase 1 knockdown on platelets and parturition.
Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1-derived (PGHS1-derived) thromboxane A(2) (TxA(2)) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1(Neo/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 TxA(2) by 98% in PGHS1(Neo/Neo) mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE(2) by 75% was associated with selectively impaired inflammatory responses. PGF(2alpha) at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1(Neo/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. PGHS1(Neo/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.
Yu
Ying
Y
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Cheng
Yan
Y
Fan
Jinjin
J
Chen
Xin-Sheng
XS
Klein-Szanto
Andres
A
Fitzgerald
Garret A
GA
Funk
Colin D
CD
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D001792:Blood Platelets / Q000378:metabolism*; D051545:Cyclooxygenase 1; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D036801:Parturition / Q000502:physiology*; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000097:blood; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000378:metabolism
D008565:Membrane Proteins; D018045:Receptors, Oxytocin; D016718:Arachidonic Acid; D011374:Progesterone; D004958:Estradiol; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D001241:Aspirin