Long-term type 1 diabetes impairs decidualization and extracellular matrix remodeling during early embryonic development in mice

Abstract

Introduction: Endometrial decidualization and associated extracellular matrix (ECM) remodeling are critical events to the establishment of the maternal-fetal interface and successful pregnancy. Here, we investigated the impact of type 1 diabetes on these processes during early embryonic development, in order to contribute to the understanding of the maternal factors associated to diabetic embryopathies.

Methods: Alloxan-induced diabetic Swiss female mice were bred after different periods of time to determine the effects of diabetes progression on the development of gestational complications. Furthermore, the analyses focused on decidual development as well as mRNA expression, protein deposition and ultrastructural organization of decidual ECM.

Results: Decreased number of implantation sites and decidual dimensions were observed in the group mated 90-110 days after diabetes induction (D), but not in the 50-70D group. Picrosirius staining showed augmentation in the fibrillar collagen network in the 90-110D group and, following immunohistochemical examination, that this was associated with increase in types I and V collagens and decrease in type III collagen and collagen-associated proteoglycans biglycan and lumican. qPCR, however, demonstrated that only type I collagen mRNA levels were increased in the diabetic group. Alterations in the molecular ratio among distinct collagen types and proteoglycans were associated with abnormal collagen fibrillogenesis, analyzed by transmission electron microscopy.

Conclusions: Our results support the concept that the development of pregnancy complications is directly related with duration of diabetes (progression of the disease), and that this is a consequence of both systemic factors (i.e. disturbed maternal endocrine-metabolic profile) and uterine factors, including impaired decidualization and ECM remodeling.

Keywords: D; Decidua; ECM; ELISA; Early embryonic development; Extracellular matrix; GAPDH; IL11; MMP; Maternal–fetal interface; Mouse; PBS; Pregnancy; SLRPs; Type 1 diabetes; days after diabetes induction; enzyme-linked immunosorbent assay; extracellular matrix; glyceraldehyde-3-phosphate dehydrogenase; hours of pregnancy; hp; interleukin 11; matrix metalloproteinase; phosphate buffered saline; qPCR; quantitative real time PCR; small leucine rich proteoglycans.