The uterine proteoglycan expression in pregnancy and labor

Objective: Protracted labor is a common clinical problem causing maternal and fetal complications. It is the leading indication for caesarean sections throughout the world, and emphasizes our need to be able to control labor. Our hypothesis is that proteoglycans in the extracellular matrix of the uterus take part of the regulation of myometrial contractions. Gap junctions play a significant role in the cell to cell communication between the myometrial smooth muscle cells. The aim of this study was to investigate the distribution of uterine proteoglycans and their role in the regulation of myometrial contractility during normal and dysfunctional labor.

Methods: Uterine specimen were collected from non-pregnant, term-pregnant, and from women in normal and dysfunctional labor. Proteoglycans were extracted with guanidinium chloride and precipitated with Alcian Blue. Separation of proteoglycans by gel- or ion-exchange chromatography was performed. The small dermatan sulphate proteoglycans were separated on a column of octylsepharose. Electrophoresis on agarose gel or on SDS-PAGE separated the proteoglycans further and western blot using specific antibodies were used for identification. Immunohistochemistry revealed the localization of the proteoglycans in the tissue. The mRNA expressions for syndecan 3 and connexin 43 were measured by real time RT-PCR. Statistical methods used were student t-test, ANOVA, Tukey HSD and Mann- Whitney test.

Results: Several proteoglycans were found in the human uterus. Decorin and biglycan constitute 80% and heparan sulphate proteoglycans 20% of the total amount. Versican was found in small amounts. During pregnancy a significant 36 % decrease of the concentration of the small dermatan proteoglycans occur. The heparan sulphate proteoglycan concentration increased by 46% during active labor. Identification of heparan sulphate proteoglycans revealed the presence of syndecan 1-4, glypican 1 and perlecan. Syndecan 3 is the most abundant heparan sulphate proteoglycan in human uterus and show the most interesting features. Its mRNA expression increases during normal labor but show a 60 % lower level during dysfunctional labor. In dysfunctional labor an irregular distribution of syndecan 3 is seen in the smooth muscle. The gap junction protein connexin 43 mRNA expression present similar changes as syndecan 3 during pregnancy and labor.

Conclusion: Our data suggest a role for heparan sulphate proteoglycans, and in particular syndecan 3, in the process of labor. One mechanism might be through regulation of the gap junction formation or function.

List of scientific papers

I. Hjelm A, Ekman-Ordeberg G, Barchan K, Malmstrom A. (2001). Identification of the major proteoglycans from human myometrium. Acta Obstet Gynecol Scand. 80(12):1084-90.
https://pubmed.ncbi.nlm.nih.gov/11846703

II. Hjelm AM, Barchan K, Malmstrom A, Ekman-Ordeberg GE. (2002). Changes of the uterine proteoglycan distribution at term pregnancy and during labour. Eur J Obstet Gynecol Reprod Biol. 100(2):146-51.
https://pubmed.ncbi.nlm.nih.gov/11750954

III. Hjelm Cluff A, Malmstrom A, Tingaker B, David G, Ekman-Ordeberg G. (2003). Normal labor associated with changes in uterine heparan sulphate proteoglycans expression and localization. Acta Obstet Gynecol Scand. [Accepted]

IV. Hjelm Cluff A, Bystrom B, Cebers G, Malmstrom A, Ekman-Ordeberg G. (2003). Expression of Syndecan 3 in relation to Connexin 43 in human uterine tissue during normal and dysfunctional labor. [Manuscript]