Abstract
BackgroundIn humans trophoblast invasion and vascular remodeling are critical to determine the fate of pregnancy. Since guinea-pigs share with women an extensive migration of the trophoblasts through the decidua and uterine arteries, and a haemomonochorial placenta, this species was used to evaluate the spatio-temporal expression of three enzymes that have been associated to trophoblast invasion, MMP-2, MMP-9 and tissue kallikrein (K1).MethodsUteroplacental units were collected from early to term pregnancy. MMP-2, MMP-9 and K1 were analysed by immunohistochemistry and Western blot. The activities of MMP-2 and MMP-9 were assessed by gelatin zymography.ResultsImmunoreactive MMP-2, MMP-9 and K1 were detected in the subplacenta, interlobar and labyrinthine placenta, syncytial sprouts and syncytial streamers throughout pregnancy. In late pregnancy, perivascular or intramural trophoblasts expressed the three enzymes. The intensity of the signal in syncytial streamers was increased in mid and late pregnancy for MMP-2, decreased in late pregnancy for MMP-9, and remained stable for K1. Western blots of placental homogenates at days 20, 40 and 60 of pregnancy identified bands with the molecular weights of MMP-2, MMP-9 and K1. MMP-2 expression remained constant throughout gestation. In contrast, MMP-9 and K1 attained their highest expression during midgestation. Placental homogenates of 20, 40 and 60 days yielded bands of gelatinase activity that were compatible with MMP-2 and MMP-9 activities. ProMMP-2 and MMP-9 activities did not vary along pregnancy, while MMP-2 and MMP-9 increased at 40 and 40–60 days respectively.ConclusionThe spatio-temporal expression of MMPs and K1 supports a relevant role of these proteins in trophoblast invasion, vascular remodeling and placental angiogenesis, and suggests a functional association between K1 and MMP-9 activation.
Highlights
In humans trophoblast invasion and vascular remodeling are critical to determine the fate of pregnancy
The spatio-temporal expression of matrix metalloproteinases (MMPs) and K1 supports a relevant role of these proteins in trophoblast invasion, vascular remodeling and placental angiogenesis, and suggests a functional association between K1 and MMP-9 activation
Two of the most studied members of this family are MMP-2 and MMP-9, which degrade a wide range of substrates, including type IV collagen, the main type of collagen found in basement membranes
Summary
In humans trophoblast invasion and vascular remodeling are critical to determine the fate of pregnancy. The establishment of pregnancy requires that trophoblasts attach to the uterine epithelium, invade the endometrium, colonize the spiral arteries and acquire an endothelial phenotype, to establish a continuum between the intervillous space and the maternal circulation [1,2]. The disturbance of these tightly spatio-temporally regulated processes causes important obstetrical and neonatal (page number not for citation purposes). Several studies have provided evidence that invasive trophoblasts secrete matrix metalloproteinases (MMPs), a family of Zn2+-dependent endopeptidases that degrade extracellular matrix (ECM) and basement membrane components [5,6]. MMP-2, MMP-9 and TIMPs are expressed in human, sheep, rat and mice reproductive tissues, and have been implicated in the invasion and development of the placental fetal villous tree; in addition, these proteins participate in the detachment of the placenta and membranes in labor [7,8,9,10,11,12,13,14,15]
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