1,326 publications from this institution
Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice
VEGF is a prototype angiogenic factor, but recent evidence indicates that this growth factor also has direct effects on neural cells. Abnormal regulation of VEGF expression has now been implicated in several neurodegenerative disorders, including motoneuron degeneration. This has stimulated an increasing interest in assessing the therapeutic potential of VEGF as a neuroprotective agent for such neurodegenerative disorders.
Novel gene technologies have allowed to manipulate the genetic balance of candidate molecules in mice in a controllable manner. Homologous or site-specific recombination in embryonic stem cells allows to study the consequences of deficiencies, mutations, conditional or tissue specific expression of gene products in transgenic mice. These technological breakthroughs have significantly advanced biomedical research and our understanding of the pathophysiological role of candidate disease genes. In addition, gene transfer allows to test the possible therapeutic use of gene products for gene therapy. With the advent of genome sequencing programs, these gene technologies provide means to study gene function in a conclusive manner. Furthermore, disease models can be generated which can be used as testmodels for (gene) therapy or for discovery of novel genes using differential gene profiling techniques. The present review will focus on the use of these technologies to study the molecular basis of how blood vessels form (angiogenesis) and how vessels can become affected by disorders. A selected number of molecules that have been studied in our laboratory will be reviewed in particular.
It has been proposed that the urokinase receptor (u-PAR) is essential for the various biological roles of urokinase-type plasminogen activator (u-PA) in vivo, and that smooth muscle cells require u-PA for migration during arterial neointima formation. The present study was undertaken to evaluate the role of u-PAR during this process in mice with targeted disruption of the u-PAR gene (u-PAR−/−). Surprisingly, u-PAR deficiency did not affect arterial neointima formation, neointimal cell accumulation, or migration of smooth muscle cells. Indeed, topographic analysis of arterial wound healing after electric injury revealed that u-PAR−/− smooth muscle cells, originating from the uninjured borders, migrated over a similar distance and at a similar rate into the necrotic center of the wound as wild-type (u-PAR+/+) smooth muscle cells. In addition, u-PAR deficiency did not impair migration of wounded cultured smooth muscle cells in vitro. There were no genotypic differences in reendothelialization of the vascular wound. The minimal role of u-PAR in smooth muscle cell migration was not because of absent expression, since wild-type smooth muscle cells expressed u-PAR mRNA and functional receptor in vitro and in vivo. Pericellular plasmin proteolysis, evaluated by degradation of 125I-labeled fibrin and activation of zymogen matrix metalloproteinases, was similar for u-PAR−/− and u-PAR+/+ cells. Immunoelectron microscopy of injured arteries in vivo revealed that u-PA was bound on the cell surface of u-PAR+/+ cells, whereas it was present in the pericellular space around u-PAR−/− cells. Taken together, these results suggest that binding of u-PA to u-PAR is not required to provide sufficient pericellular u-PA–mediated plasmin proteolysis to allow cellular migration into a vascular wound.
Abstract The role of proteinases in the mobilization of hematopoietic progenitor cells (HPCs) after granulocyte colony-stimulating factor (G-CSF) remains unclear. Here we report that genetic loss of the plasminogen activator inhibitor Pai-1 or of the plasmin inhibitor α2-antiplasmin increases HPC mobilization in response to G-CSF. Moreover, thrombolytic agents, such as tenecteplase and microplasmin, enhance HPC mobilization in mice and humans. Taken together, these findings identify a novel role for plasmin in augmenting HPC mobilization in response to G-CSF.
