Harris Lynda K, Keogh Rosemary J, Wareing Mark, Baker Philip N, Cartwright Judith E, Aplin John D, Whitley Guy St J
Maternal and Fetal Health Research Centre, Division of Human Development, University of Manchester, St. Mary's Hospital, Manchester, UK.
Am J Pathol. 2006 Nov;169(5):1863-74. doi: 10.2353/ajpath.2006.060265.
During pregnancy, trophoblasts migrate from the placenta into uterine spiral arteries, transforming them into wide channels that lack vasoconstrictive properties. In pathological pregnancies, this process is incomplete. To define the fundamental events involved in spiral artery remodeling, we have studied the effect of trophoblasts on vascular smooth muscle cells (SMCs). Here we demonstrate for the first time that apoptosis of SMCs can be initiated by invading trophoblasts. When trophoblasts isolated from normal placenta (primary trophoblasts) or conditioned medium was perfused into spiral or umbilical artery segments, apoptosis of SMCs resulted. Culture of human aortic SMCs (HASMCs) with primary trophoblasts, primary trophoblast-conditioned medium, or a trophoblast-derived cell line (SGHPL-4) also significantly increased SMC apoptosis. Fas is expressed by spiral artery SMCs, and a Fas-activating antibody triggered HASMC apoptosis. Furthermore, a Fas ligand (FasL)-blocking antibody significantly inhibited HASMC apoptosis induced by primary trophoblasts, SGHPL-4, or trophoblast-conditioned medium. Depleting primary trophoblast-conditioned medium of FasL also abrogated SMC apoptosis in vessels in situ. These results suggest that apoptosis triggered by the release of soluble FasL from invading trophoblasts contributes to the loss of smooth muscle from the walls of spiral arteries during pregnancy.
在孕期，滋养层细胞从胎盘迁移至子宫螺旋动脉，将其转变为缺乏血管收缩特性的宽阔通道。在病理性妊娠中，这一过程并不完整。为了明确螺旋动脉重塑所涉及的基本事件，我们研究了滋养层细胞对血管平滑肌细胞（SMC）的影响。在此我们首次证明，侵入的滋养层细胞可引发SMC凋亡。当将从正常胎盘分离出的滋养层细胞（原代滋养层细胞）或条件培养基灌注到螺旋动脉或脐动脉节段时，会导致SMC凋亡。用人主动脉SMC（HASMC）与原代滋养层细胞、原代滋养层细胞条件培养基或一种滋养层来源的细胞系（SGHPL-4）共同培养，也显著增加了SMC凋亡。Fas在螺旋动脉SMC中表达，一种Fas激活抗体可引发HASMC凋亡。此外，一种Fas配体（FasL）阻断抗体显著抑制了原代滋养层细胞、SGHPL-4或滋养层细胞条件培养基诱导的HASMC凋亡。去除原代滋养层细胞条件培养基中的FasL也消除了原位血管中的SMC凋亡。这些结果表明，侵入的滋养层细胞释放可溶性FasL引发的凋亡，促成了孕期螺旋动脉壁平滑肌的丧失。
