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1 Department of Anatomy, Universitaetsklinikum Benjamin Franklin, Freie Universitaet Berlin, Berlin, Germany; Department of Physiology, Universitaetsklinikum Benjamin Franklin, Freie Universitaet Berlin, Berlin, Germany
2 Department of Physiology, Universitaetsklinikum Benjamin Franklin, Freie Universitaet Berlin, Berlin, Germany
3 Department of Anatomy, Universitaetsklinikum Benjamin Franklin, Freie Universitaet Berlin, Berlin, Germany
* To whom correspondence should be addressed. E-mail: olibaum{at}zedat.fu-berlin.de.
The increase of wall shear stress in capillaries by oral administration of the alpha1-adrenergic receptor antagonist prazosin induces angiogenesis in skeletal muscles. Since endothelial nitric oxide synthase (eNOS) is up-regulated in response to elevated wall shear stress we investigated the relevance of eNOS for prazosin-induced angiogenesis in skeletal muscles. Prazosin and/or the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (L-NAME) were given to C57Bl/6 wild-type mice and eNOS knockout-mice for up to 14 days. The capillary/fiber-ratio (C/F-ratio) and capillary density (CD; number of capillaries per mm2) were determined in frozen sections from extensor digitorum longus muscles (EDL) of these mice. Immunoblotting was performed to quantify eNOS expression in endothelial cells isolated from skeletal muscles whereas VEGF (after precipitation with heparin-agarose) and nNOS concentrations were determined in EDL solubilisates. In EDL of C57 mice treated for 14 days, C/F-ratio was 28% higher after administration with prazosin and 11% higher after feeding with prazosin and L-NAME while the CD was increased by 21% and 13%, respectively. C/F-ratio was highest after day 4 of prazosin treatment followed by a gradual decrease to almost constant values after day 8. Prazosin administration led to an elevation of eNOS expression. Levels of VEGF were lowest at day 4 while nNOS decreased after day 8. In EDL of eNOS knockout-mice, no significant changes in C/F-ratio, CD and expression of VEGF and nNOS were observed in response to prazosin administration. Our data suggest that the presence of eNOS is essential for prazosin-induced angiogenesis in skeletal muscle albeit other signaling molecules might partially compensate for/contribute to this angiogenic activity. Furthermore, subsequent remodeling of the capillary system accompanied by sequential down-regulation of VEGF and nNOS in skeletal muscle fibers characterizes shear stress-dependent angiogenesis.
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