POSTIMPLANTATION MODIFICATION OF THE SPIRAL ARTERIES

螺旋动脉的植入后改造

• 批准号: 2199194
• 负责人: BARRY F KING
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2199194
• 关键词: Macaca fascicularis; Macaca mulatta; artery; cell adhesion molecules; cell cell interaction; cell migration; extracellular matrix; histochemistry /cytochemistry; immunocytochemistry; integrins; mixed tissue /cell culture; nonsurgical revascularization; preeclampsia; pregnancy circulation; pregnancy toxemia /hypertension; scanning electron microscopy; trophoblast; vascular endothelium; vascular smooth muscle

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 绒毛外滋养细胞迁移机制的研究进展 进入母体螺旋动脉及其在修饰中的作用 动脉壁。动脉的充分侵袭和改造 似乎是为胎盘提供正常血液供应所必需的。 不充分的侵袭和重塑与怀孕有关。 并发高血压和宫内发育迟缓，并有 被认为是流产的原因之一。因为有局限性 与获得精确发育的人类材料有关 年龄，而且这种类型的入侵只发生在更高的 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，有三个具体目的 将探索三个相关的假设：i) 滋养层细胞利用细胞-细胞黏附分子系统 沿着母体内皮细胞迁移。鉴于我们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黏附，几乎没有 已知滋养层细胞与内皮细胞的相互作用。我们将研究 免疫细胞化学结合的这种相互作用的分子基础 定位以确定什么黏附分子存在于原位和 用体外细胞黏附实验验证它们的功能参与。 2)滋养层细胞利用细胞外基质(ECM)和一个家族 基质受体(整合素)作为一种入侵血管壁的手段 动脉。一旦滋养层细胞沿着动脉迁移到一些 深度，然后它们渗出并侵入动脉壁，破坏 肌肉和细胞外基质成分。在实现这一目标的过程中，我们 假设细胞与基底中的细胞外基质成分相互作用 膜和其他地方，使用这些相互作用作为粘连的基础 或迁徙。我们将确定动脉中存在的细胞外基质的类型 WALL，它们如何改变以响应入侵，以及如何整合 当细胞侵入动脉壁时，表达受到调节。团结在一起， 这两个具体目标的结果应该会提供重要的新见解 关于滋养层细胞实现这一目标的分子机制 生理上重要的过程。最后，我们假设 螺旋动脉壁中的滋养层细胞仍有功能 活性物质，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液。我们的 初步研究表明，免疫反应性内皮素的存在- 1，一种有效的血管收缩物质，以及一种有效的降钙素基因相关肽 血管扩张剂，在许多滋养层细胞的螺旋壁中 动脉。本提案中概述的实验将证实并延长 这些观察结果。猕猴是一种极好的探索动物 这一假设和我们的发现应该会增加关于 调节母体向胎盘供血的潜在因素。