Molecular and cellular biology of the urokinase/urokinase receptor -related vascular remodeling

这项建议阐述了多功能尿激酶(UPA)/尿激酶受体(UPAR)系统在血管重塑中的作用。我们最近的研究主要由最初的DFG拨款支持，表明uPAR在调节人血管平滑肌细胞(VSMC)表型变化方面具有新的功能，VSMC是血管重塑的关键事件。我们发现，uPAR可以主动控制VSMC从生理分化到病理生理去分化的表型。到目前为止，我们还不知道uPAR的这种功能。此外，我们发现uPAR可能转位到细胞核，在那里它与肌钙蛋白结合，肌钙蛋白是一种血清反应因子(SRF)辅助因子，在血管和心肌细胞系中特异表达，在体内VSMC分化中起重要作用。我们现在假设，uPAR通过肌钙蛋白和肌卡丁相关转录因子(MRTF)调节依赖于SRF的转录调控元件，控制SMC收缩基因的表达。阐明潜在的分子机制及其在体内的功能生理后果构成了本提案的主要目标。

This proposal addresses a role of the multifunctional urokinase (uPA)/urokinase receptor (uPAR) system in vascular remodeling. Our recent studies supported mainly by the initial DFG grant suggest a novel function for uPAR in regulation of phenotypic changes of human vascular smooth muscle cells (VSMC), a key event of vascular remodeling. We found that uPAR provides an active control of the VSMC modulation from a physiological differentiated to a pathophysiological de-differentiated phenotype. This function of uPAR has not been known so far. Furthermore, we revealed that uPAR might translocate to the cell nucleus where it associates with myocardin, a serum response factor (SRF) cofactor that is expressed specifically in smooth and cardiac muscle lineages and plays an important role in VSMC differentiation in vivo. We hypothesize now that uPAR, via myocardin and the myocardinrelated transcription factors (MRTFs), modulates SRF-dependent transcriptional regulatory elements controlling expression of SMC contractile genes. The elucidation of underlying molecular machinery and its functional physiological consequences in vivo constitutes a major goal of the present proposal.