Pregnancy of bovine clones and the enigma of the preeclampsia syndrome: development of an experimental model to study vascular disorders in the uterus and placenta

Abstract

The ability to produce viable products by SCNT provides remarkable new perspectives in animal production and science. Bovine SCNT cloning is a prominent new technology, however still presents very low efficiency and high costs. Efficiency in terms of live birth in SCNT cloning in bovines is around 9% after ET. The sequence of events occurring during the two first of pregnancy is key to development. During this time, endometrial vascular stimulation guarantees an adequate uterine environment for embryo survival, maternal recognition of pregnancy, implantation, placentation, and placentome development. After that, uterine tissue and vascular remodeling will continue throughout pregnancy in parallel to fetal development as requirements increase. During all losses, the observed macroscopic pathologies are clearly related to vascular disturbances. Our previous work in mares and cows clearly demonstrated the efficiency and reliability of the Doppler ultrasound technique to assess uterine and conceptus vascular changes during early pregnancy. The first research objective of this proposal aims to develop an approach to predict pregnancy outcome early in gestation in SCNT cloning by assessing vascular perfusion non-invasively with Doppler ultrasonography. This project will provide a detailed description of all uterine, embryonic, placental, and fetal vascular changes during pregnancy in SCNT cloned and natural-produced embryos. A mapping of all placental and fetal vascular and morphological changes will be done, and key points for future studies using molecular and cellular biology approaches to explain the regulation of these changes will be identified. In addition, special attention will be given to the expected correlation between these compensatories changes during the periods of high requirements for placental exchanges with the data collected at the placentation time. The second research objective of this proposal aims to study deeply late pregnancy in bovine SCNT cloned embryo pregnancies. Pregnancies of SCNT clones are associated with large offspring syndrome (or large placenta syndrome), hydrallantois, placentomegaly, fetal edema (head, umbilical cord, anasarca, and others). In addition, this period coincides with an increase in fetal growth rate when the placenta is challenged more and more to supply the fetal demands until term. In SCNT pregnancies, probably the impaired placenta is not capable of responding, resulting in abnormal or inadequate morphological development. Expression of factors related to placenta vascular development and remodeling is probably unbalanced and uncontrolled, being the cause of the observed pathologies. This physiopathology described in clones suggests some similarities with preeclampsia syndrome in women. Preeclampsia occurs in an estimated 3-5% of births, and is a leading cause of both fetal and maternal morbidity and mortality worldwide. It has been suggested that up-regulation of vascular related factors expression in preeclamptic women will release abnormal amount of soluble factors in the maternal blood system causing the systemic disturbances as hypertension and proteinuria. This proposal suggests that the pathophysiology of the problems in preeclamptic women and SCNT pregnant cows may be similar. However, the different kind of placentation between the two species may explain the presence of systemic effects in human mothers, but not in cows. That is, the hemochorial placenta in women permits release of the factors in the maternal blood and the synepitheliochorial placenta in cows restrict the presence of the soluble factors inside of the placental area and fetus. If the similarities between the physiopathology of preeclampsia and pathologies of late pregnancy in bovine SCNT cloning were proven, the knowledge of the mechanisms involved in these process will give us a useful animal model for future preeclampsia studies. (AU)