Fonseca B M, Correia-da-Silva G, Teixeira N A
UCIBIO, REQUIMTE, Laboratório de Bioquímica, Departamento Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
UCIBIO, REQUIMTE, Laboratório de Bioquímica, Departamento Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Mol Cell Endocrinol. 2015 Aug 15;411:167-76. doi: 10.1016/j.mce.2015.04.024. Epub 2015 May 7.
The major endocannabinoid, anandamide (AEA), is widely distributed in the body, especially in the reproductive tissues, where it is implicated in early pregnancy events, particularly during implantation period. Although AEA is synthesized in decidual cells and showed to induce apoptosis through CB1 receptor, its roles in decidualization remain to be elucidated. This study examined the effect of AEA in the progression of decidualization both in vitro and in vivo and explored the involvement of COX-2 in its action. To determine the function of AEA during this differentiation process, we employed a primary culture system in which undifferentiated stromal cells isolated from pregnant rat uterus undergo decidualization. AEA treatment markedly interfered with the differentiation program, as revealed by α2-macroglobulin (α2-MG) expression and alkaline phosphatase activity. Additionally, it was evaluated the effects of AEA in decidual establishment in the pseudopregnant rat model. The abundance of AEA in the uterine lumen disrupted the decidualization process accompanied by a decreased expression of COX-2 and VEGF. It was also observed that uterine lumen, which failed the progression of decidualization in response to AEA, also presented lower expression of NAPE-PLD and FAAH. Thus, the mechanisms by which AEA inhibits decidualization can be either via direct actions on stromal cell differentiation within the reproductive tract system or by the inhibition of COX-2 derived products and, consequently, the vascular remodeling required to proper decidualization. In addition, the previous observations showing that higher AEA levels in pre-implantation sites are hostile to blastocyst survival may result from problems in decidual cell reaction more than with implantation failure.
主要内源性大麻素——花生四烯酸乙醇胺（AEA）广泛分布于体内，尤其是在生殖组织中，它与早期妊娠事件有关，特别是在着床期。尽管AEA在蜕膜细胞中合成，并显示通过CB1受体诱导细胞凋亡，但其在蜕膜化过程中的作用仍有待阐明。本研究检测了AEA在体内外蜕膜化进程中的作用，并探讨了COX-2在其作用中的参与情况。为了确定AEA在这一分化过程中的功能，我们采用了一种原代培养系统，其中从妊娠大鼠子宫分离的未分化基质细胞会发生蜕膜化。如α2-巨球蛋白（α2-MG）表达和碱性磷酸酶活性所示，AEA处理显著干扰了分化程序。此外，还评估了AEA在假孕大鼠模型中蜕膜形成的作用。子宫腔内AEA的丰度破坏了蜕膜化过程，同时伴有COX-2和血管内皮生长因子（VEGF）表达降低。还观察到，因AEA而未能发生蜕膜化进程的子宫腔，其N-酰基磷脂乙醇胺特异性磷脂酶D（NAPE-PLD）和脂肪酸酰胺水解酶（FAAH）的表达也较低。因此，AEA抑制蜕膜化的机制可能是通过直接作用于生殖道系统内的基质细胞分化，或通过抑制COX-2衍生产物，进而抑制适当蜕膜化所需的血管重塑。此外，先前的观察表明，着床前部位较高的AEA水平对囊胚存活不利，这可能更多是由于蜕膜细胞反应问题而非着床失败所致。
