RELAXIN: BIOCHEMICAL AND PHYSIOLOGICAL STUDIES

在人类和其他哺乳动物的怀孕后期

During late pregnancy in humans and other mammalian species, the consistency of cervical connective tissue softens thus, enabling cervical dilatation and rapid delivery of the fetus(es). In cases of difficult spontaneous delivery or induced delivery at term, a hard inelastic cervix may be a source of complications. The hormone relaxin is an effective cervical softening agent with potential for clinical application in women and domestic animals. Informed decisions concerning the use of relaxin as a softening agent will largely depend upon basic studies of its effects in species other than the human. The principal long-range objective of this application is to better understand, at the molecular level, the mechanism(s) whereby relaxin, through effects upon the connective tissue, promotes softening of the cervix in the pregnant rat. The specific aims will be to identify, isolate, and chazacterize proteoglycans whose synthesis is stimulated by relaxin. Additionally, the influence of relaxin on key enzymes involved with the synthesis and degradation of cervical collagen will be determined. Rats will be ovariectomized on day 9 of pregnancy and thereafter receive hormone replacement therapy with physiological levels of progesterone and estrogen--with and without relaxin. Cervices will be collected late in pregnancy (day 22). Major efforts will be made to determine relaxin's effects not only on entire cervices obtained from intact rats (in vivo studies) but also on cervical tissue explants and primary cultures of relaxin- responsive cervical cells (in vitro studies). The influence of relaxin on both cellular and extracellular cervical components will be determined at the light and electron microscope level. To accomplish this aim, passive neurralization with monoclonal antibodies specific for rat relaxin will be done to deprive pregnant rats of endogenous relaxin during the second half of pregnancy. A second objective of this application is to determine whether the widely held (but unsubstantiated) hypothesis that relaxin, through its effects upon growth and connective tissue remodeling of the rat uterine horns, plays an important role in accommodating the developing fetuses is correct. The speciiic aims will be to determine the consequences of deprivation of endogenous relaxin following passive neutralization of relaxin with monoclonal antibodies specific for rat relaxin on the growth and composition of the uterine horns as well as the growth and vitality of the fetuses during late pregnancy.