Pregnancy

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) suffering from excessive erythrocytosis generally abort at mid-gestation 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 to wild type (wt) littermates. Consequently, uterine artery growth was reduced and dramatically less viable pups (1.63 ± 2.20 vs. 8.10 ± 0.74 in wt) of lower weight (1.29 ± 0.07g vs. 1.62 ± 0.12g 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 to wt. We conclude that poor arteriogenesis is a previously unappreciated cause for clinically important pregnancy complications.

Key words: Female Reproductive Tract • Pregnancy • intrauterine growth retardation • repeated pregnancy loss