Understanding the molecular mechanisms underlying uterine spiral artery remodeling, a critical process for pregnancy and fetal well-being: importance of chymases.

深入了解成功妊娠和胎儿发育不受限制的机制至关重要。最佳的、不受限制的宫内发育不仅对人类的生存很重要，而且是成人健康和疾病的基础。妊娠早期一个非常重要的过程是母体螺旋动脉（SA）的重塑，将母体血液输送到胎盘，为胎儿提供必需的营养和氧气。我们以前的研究表明肥大细胞（MC）及其介质糜酶对SA的适当重塑的重要性。MC或其介体的缺乏导致小鼠中显著的子宫内生长受限。我们可以证明，口服避孕药中存在的内分泌干扰化合物17-α-乙炔基炔雌醇（EE 2）在环境中的浓度不断增加，对小鼠的SA重塑产生负面影响。这些观察结果背后的原因还远未被理解。该项目的总体目标是了解MC和糜酶对SA重塑的积极影响中涉及的机制和调控途径，SA重塑是妊娠和胎儿健康的关键过程。特别是，我的目的是调查的影响MC和凝乳酶的细胞过程与子宫血管生成，特别是SA重塑过程，哪些因素调节和影响凝乳酶产生细胞的功能。 以下科学问题将得到解决：1）MC/糜酶是否调节血管平滑肌细胞、细胞外基质、绒毛外滋养层细胞或血管生成的行为或功能，这些都是SA重塑过程的重要因素？2)雌激素EE 2是否干扰SA重塑过程中MC/糜酶的特定过程？3)凝乳酶产生细胞上雌激素受体的阻断是如何影响卵巢功能的？我研究的长期目标是揭示对未出生生命的负面影响。确切的SA重塑机制和潜在因素的知识是改善妊娠疾病治疗的基础，这对全世界的人类都是很重要的。该项目的实现也将预期国外生殖免疫学的成果，因为它们具有很高的跨学科潜力。随着肿瘤和过敏性疾病的急剧增加，增加对MC领域的了解至关重要。 关于内分泌干扰物（如EE 2）的新研究结果也很有用，因为这些物质是社会上主要健康利益目标的主题。

The profound understanding of the mechanisms underlying a successful pregnancy and an un-restricted fetal development are of crucial importance. The optimal, unrestricted intrauterine de-velopment is not only important for the survival of our specie; it is the fundament of adult health and diseases. A very important process during early pregnancy is the remodeling of the maternal spiral arteries (SAs) that transport maternal blood to the placenta to provide essential nutrients and oxygen for the fetus. Our previous studies demonstrate the importance of mast cells (MCs) and their media-tor chymase for a proper SA remodeling. The absence of MCs or their mediator(s) results in dramatic intrauterine growth restriction in mice. We could show that the endocrine disrupting chemical compound 17--ethinylestradiol (EE2), present in oral contraceptives and present at increasing concentrations in the environment, negatively influences the SA remodeling in mice. The reasons underlying these observations are far from being understood. The overall goal of this project is to understand the mechanisms and regulatory pathways in-volved in the positive effects of MCs and chymases on SA remodeling, a critical process for pregnancy and fetal well-being. In particular I aim to investigate the influence of MCs and chy-mases on the cellular processes associated with uterine angiogenesis, in particular SA remodel-ing processes and which factors regulate and influence the function of chymase-producing cells. The following scientific questions will be addressed:1) Do MCs/chymases modulate the behavior or the function of vascular smooth muscle cells, the extracellular matrix, extravillous trophoblasts or angiogenesis, that are all important factors for the SA remodeling process?2) Does the estrogenic substance EE2 interfere with MCs/chymases on specific processes dur-ing SA remodeling?3) How does the blockage of estrogen receptors on chymase-producing cells affect pregnacy?The long-term objective of my research is to reveal negative influences on unborn life. Knowledge of the exact SA remodeling mechanisms and the underlying factors is the basis for therapeutic improvements for pregnancy disorders that are substantial for humans worldwide. The realization of this project will also anticipate results abroad from reproductive immunology as they have a high interdisciplinary potential. Increasing knowledge in the field of MCs is of crucial important as tumor and allergic diseases increase drastically. Also new research results con-cerning endocrine disruptors like EE2 are useful as these substances are subject of major health interest target in the society.