POSTIMPLANTATION MODIFICATION OF THE SPIRAL ARTERIES

螺旋动脉的植入后改造

基本信息

批准号：
2403177
负责人：
ALLEN C ENDERS
金额：
$ 17.6万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-03-01 至 1999-08-31
项目状态：
已结题

项目摘要

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.

该项目的长期目标是确定细胞绒毛外滋养层细胞迁移的机制进入母体螺旋动脉及其在改变动脉壁。充分侵入和改变动脉似乎有必要为胎盘提供正常的血液供应。侵袭和重塑不足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。由于限制与精确发育时获取人类物质有关年龄，事实上这种类型的入侵只发生在更高的灵长类动物，我们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标提出将探索三个相关假设：I）滋养层细胞利用细胞间粘附分子系统沿着母体内皮迁移。尽管已经学到了很多东西关于白细胞和肿瘤细胞与内皮细胞的粘附，知之甚少。已知有关滋养层-内皮相互作用。我们将检查这种相互作用的分子基础是免疫细胞化学的组合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其功能参与。 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某些部位深度，然后它们外渗并侵入动脉壁，破坏肌肉和 ECM 成分。在实现这一目标的过程中，我们假设细胞与地下室的 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迁移。我们将确定动脉中存在的 ECM 类型墙，这些变化如何响应入侵，以及整合素如何当细胞侵入动脉壁时表达受到调节。在一起，这两个具体目标的结果应该提供重要的新见解关于滋养层用于实现这一目标的分子机制重要的生理过程。最后，3）我们假设螺旋动脉壁中的滋养层细胞保持功能具有活性，可能是发挥作用的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。我们的初步研究表明存在免疫反应性内皮素 1、强效血管收缩剂和降钙素基因相关肽，强效血管收缩剂血管扩张剂，存在于螺旋壁的许多滋养层细胞中动脉。本提案中概述的实验将确认并扩展这些观察结果。猕猴是一种极好的探索动物这个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。