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

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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.