POSTIMPLANTATION MODIFICATION OF THE SPIRAL ARTERIES

该项目的长期目标是确定蜂窝 绒毛外滋养层细胞迁移的机制 进入母体螺旋动脉及其在修改 动脉壁充分侵入和修改动脉 似乎是为胎盘提供正常血液供应所必需的 不充分的侵入和重塑与怀孕有关 并发高血压和胎儿宫内发育迟缓， 被认为是流产的原因。由于局限性 与人类物质的获得有关， 年龄，事实上，这种类型的入侵只发生在较高的 灵长类动物，我们已经使用猕猴动物模型来探索细胞 这种现象的生物学。在本申请中，三个具体目的是 提出将探讨三个相关的假设：一）， 滋养层细胞利用细胞-细胞粘附分子系统， 沿着母体内皮迁移。尽管我们已经了解了很多 关于白细胞和肿瘤细胞与内皮细胞的粘附， 关于滋养层-内皮细胞相互作用的研究。我们会研究 这种相互作用的分子基础结合免疫细胞化学 定位以确定原位存在哪些粘附分子， 使用体外细胞粘附测定验证它们的功能参与。 2)滋养层利用细胞外基质（ECM）和一个家族， 基质受体（整合素）作为侵入细胞壁的手段， 动脉一旦滋养层细胞沿着动脉迁移到一些 当它们进入深度时，它们就会外渗并侵入动脉壁， 肌肉和ECM成分。在实现这一目标的过程中，我们 假设细胞与基底中的ECM成分相互作用 膜和其他地方，使用这些相互作用作为粘附的基础 或移民。我们将确定动脉中存在的ECM类型 这些细胞如何在入侵时发生变化，以及整合素 表达随着细胞侵入动脉壁而被调节。统称 这两个具体目标的结果应该提供重要的新见解 至于滋养层用来实现这一点的分子机制， 重要的生理过程。最后，我们假设， 螺旋动脉壁中的滋养层细胞在功能上 可能是血管活性物质的来源， 局部或区域性地调节流向胎盘的母体血流。我们 初步研究表明存在免疫反应性内皮素- 1，一种有效的血管收缩剂，和降钙素基因相关肽，一种有效的 血管扩张剂，在螺旋壁的许多滋养层细胞中 动脉本提案中概述的实验将证实并扩展 这些观察。猕猴是一种很好的动物， 这一假设和我们的发现应该增加重要的新信息， 调节母体胎盘血液供应的潜在因素。

The long-term objective of the project is to determine the cellular mechanisms involved in the migration of extravillous trophoblast cells into the maternal spiral arteries and their role in the modification of the arterial wall. Adequate invasion and modification of the arteries appears necessary to provide a normal blood supply to the placenta. Inadequate invasion and remodeling has been associated with pregnancies complicated by hypertension and intrauterine growth retardation and has been suggested as a cause of miscarriages. Because of limitations associated with acquisition of human material at precise developmental ages, and the fact that this type of invasion occurs only in higher primates, we have used the macaque animal model to explore the cellular biology of this phenomenon. In the present application three specific aims are proposed that will explore three related hypotheses: I) that trophoblast cells utilize a system of cell-cell adhesion molecules to migrate along the maternal endothelium. Whereas much has been learned about leukocyte and tumor cell adhesion to endothelial cells, little is known regarding trophoblast-endothelial interactions. We will examine the molecular basis of this interaction by a combination of immunocytochemical localizations to determine what adhesion molecules are present in situ and verify their functional involvement using an in vitro cell adhesion assay. 2) that trophoblast utilizes the extracellular matrix (ECM) and a family of matrix receptors (integrins) as a means to invade the walls of the arteries. Once trophoblast cells have migrated along the artery to some depth, they then extravasate and invade the wall of the artery, disrupting the muscular and ECM components. In the process of accomplishing this, we hypothesize that the cells interact with ECM components in the basement membrane and elsewhere, using these interactions as a basis for adhesion or migration. We will determine the types of ECM present in the arterial wall, how these change in response to invasion, and how integrin expression is modulated as cells invade the arterial wall. Together, the results of these two specific aims should provide significant new insights as to the molecular mechanisms utilized by trophoblast to accomplish this physiologically important process. Finally, 3) we hypothesize that trophoblast cells in the walls of the spiral arteries remain functionally active and may be the source of vasoactive substances that could act locally or regionally to regulate maternal blood flow to the placenta. Our preliminary studies have shown the presence of immunoreactive endothelin- 1, a potent vasoconstrictor, and calcitonin gene-related peptide, a potent vasodilator, in many trophoblast cells in the walls of the spiral arteries. Experiments outlined in this proposal will confirm and extend these observations. The macaque is an excellent animal in which to explore this hypothesis and our findings should add significant new information on potential factors regulating the maternal blood supply to the placenta.