Vasculo-proliferative disorders such as atherosclerosis, postangioplasty restenosis, and pulmonary hypertension are complex processes that are especially related to vascular smooth muscle cells (VSMCs)45, 78. In the arterial media, VSMC are normally quiescent, however, for the development and progression of the above mentioned diseases it is prerequisite that quiescent VSMCs start to proliferate, migrate and undergo apoptosis. Different extracellular stimuli are responsible for regulating VSMC

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... omeostasis, including growth factors, cytokines and mechanic stress. Through activating the intracellular phosphatidylinositol 3-kinase (PI3K)/Aktpathway these factors critically regulate the transcriptional activity of the forkhead box O (FoxO) transcription factors via phosphorylation. FoxOs have crucial roles in different biological processes such as proliferation, differentiation, metabolism, aging, cell survival and stress resistance. Intervening VSMC function by affecting FoxO1a function may represent an attractive approach for future therapeutic strategies in the prevention of vasculo-proliferative diseases.Part 1: Upon Akt-mediated phosphorylation under mitogenic conditions, FoxOs depart from the nucleus. However, stabilization and localization of the ranscription factors in the nucleus is a prerequisite for executing their regulatory function. Psammaplysene A, a natural product from the marine sponge Psammaplysilla sp., was revealed to promote retention of FoxO1a in the nucleus of VSMCs by directly regulating FoxO1a localization. The marine compound was demonstrated to affect cell viability and to inhibit VSMC proliferation in vitro and in vivo by inhibiting S-phase due to attenuating cyclin D1 expression. A Psammaplysene A-analogue named F10 similarly affected VSMC behavior. By applying Psammaplysene A and F10 simultaneously, single doses of each compound could be reduced. Dysfunction of pulmonary VSMCs (PASMCs) contributes to the development of pulmonary hypertension. In Part 2 of this thesis I identified FoxO1a [...]