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

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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.