title: Abortion in mice with excessive erythrocytosis is due to impaired arteriogenesis of the uterine arcade.
abstract: We postulate that repeated pregnancy loss, intrauterine growth restriction, and preeclampsia are caused by impaired elevation of uterine blood flow due to disturbed arteriogenesis of the uterine arcade. This hypothesis is based on the observation that pregnant human erythropoietin-overexpressing (plasma levels elevated 12-fold) mice (termed tg6 mice) suffering from excessive erythrocytosis generally abort at midgestation unless their hematocrit of 0.85 is drastically lowered. Transgenic mice show placental malformations that parallel those observed in pregnant women suffering from impaired uterine perfusion. Shear stress, a key factor inducing arteriogenesis, was 5-fold lower in tg6 mice compared with wildtype (WT) littermates. Consequently, uterine artery growth was reduced, and dramatically fewer viable pups (1.63 +/- 2.20 vs. 8.10 +/- 0.74 in WT) of lower weight (1.29 +/- 0.07 g vs. 1.62 +/- 0.12 g in WT) were delivered in first pregnancies. Only in subsequent pregnancies did tg6 deliver approximately the expected number of pups. Birth weights of tg6 offspring, however, remained reduced. As the spleen is a major site of extramedullary erythropoiesis in tg6 animals, splenectomy reduced the hematocrit to 0.6-0.7. In turn, shear stress increased to normal values, and splenectomized primiparous tg6 showed normal uterine artery growth and delivery of pups similar in number and weight compared with WT. We conclude that poor arteriogenesis is a previously unappreciated cause for clinically important pregnancy complications.
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, CH-8057 Zürich, Switzerland.
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Annamaria
authors.initials: A
authors.lastname: Manini
authors.forename: Thomas
authors.initials: T
authors.lastname: Stallmach
authors.forename: Bianca
authors.initials: B
authors.lastname: Saam
authors.forename: Gisela
authors.initials: G
authors.lastname: Kuhn
authors.forename: Beat
authors.initials: B
authors.lastname: Grenacher
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Bogdanova
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogel
mesh_terms: D000022:Abortion, Spontaneous / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001158:Arteries / Q000254:growth & development; D001783:Blood Flow Velocity; D001809:Blood Viscosity; D004921:Erythropoietin / Q000235:genetics; D005260:Female; D006400:Hematocrit; D006801:Humans; D007247:Infertility, Female / Q000097:blood / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011086:Polycythemia / Q000150:complications* / Q000235:genetics; D011247:Pregnancy; D011994:Recombinant Proteins; D014599:Uterus / Q000098:blood supply*
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin