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Abortion in Mice with Excessive Erythrocytosis Is Due to Impaired Arteriogenesis of the Uterine Arcade¹

Institute of Veterinary Physiology,³ Vetsuisse Faculty and Zürich Center for Integrative Human Physiology (ZIHP), and Department of Pathology,⁴ University of Zürich, CH-8057 Zürich, Switzerland

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.

arteriogenesis, erythropoietin, female reproductive tract, fertility, intrauterine growth restriction, intrauterine growth retardation, polycythemia, preeclampsia, pregnancy, repeated pregnancy loss, uterine artery

¹Supported by the Swiss National Science Foundation (3100A0–104242), Stiftung für wissenschaftliche Forschung an der Universität Zürich, and University Research Priority Program "Integrative Human Physiology" at the ZIHP to J.V.

Correspondence: ²Johannes Vogel, Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, Winterthurerstr. 260, CH-8057 Zürich, Switzerland. FAX: 41 44 6358932; e-mail: jvogel{at}vetphys.uzh.ch