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Background: This study aims to quantify by intravital microscopy the microhemodynamic response after extracorporeal shock wave application (ESWA) to the physiologic microcirculation of the mouse dorsal skinfold chamber.Materials and Methods: ESWA was carried out using an electrohydraulic shock wave source. Two different shock wave doses of 500 and 1000 pulses at an energy flux rate of 0.08 mJ/mm2 and a frequency of 4 Hz were compared with sham-operated animals. Microcirculatory analyses were performed at baseline (BL) and during a 3 d observation period after ESWA. The expression of caspase-3 (casp-3), proliferating cell nuclear antibody (PCNA), von Willebrand factor (vWF), and endothelial nitric oxide synthase (eNOS) were analyzed semiquantitatively by immunohistochemistry.Results: ESWA provoked a significant and persistent increase of functional capillary density (FCD) throughout the observation period, reaching a maximum (140% ± 5% of BL, P < 0.05 versus sham) after 1 d when animals were treated with 1000 pulses. ESWA induced a slight increase of leukocyte rolling (not, vert, similar2-to not, vert, similar3.5-fold, P < 0.05) and leukocyte adherence (not, vert, similar1.5-to not, vert, similar2-fold, P < 0.05) to the endothelial lining of postcapillary venules. One day following ESWA, we observed enhanced expression of casp-3 (not, vert, similar3-to not, vert, similar4-fold), PCNA (not, vert, similar9-to not, vert, similar14-fold), vWF (not, vert, similar11-to not, vert, similar14-fold), and eNOS (not, vert, similar3-fold), all P < 0.05.Conclusion: This study shows that ESWA provokes a favorable persistent increase of patent capillaries, however accompanied by a transient and slight inflammatory response but also by dose-dependant apoptotic cell death. Our data suggest that ESWA might represent a noninvasive biomechanical tool to treat critically perfused and endangered tissues, but certainly warrants further investigation. Background. This study aims to quantify by intravital microscopy the microhemodynamic response after extracorporeal shock wave application (ESWA) to the physiologic microcirculation of the mouse dorsal skinfold chamber. U N C O R R E C T E D P R O O FMaterials and Methods. ESWA was carried out using an electrohydraulic shock wave source. Two different shock wave doses of 500 and 1000 pulses at an energy flux rate of 0.08 mJ/mm 2 and a frequency of 4 Hz were compared with sham-operated animals. Microcirculatory analyses were performed at baseline (BL) and during a 3 d observation period after ESWA. The expression of caspase-3 (casp-3), proliferating cell nuclear antibody (PCNA), von Willebrand factor (vWF), and endothelial nitric oxide synthase (eNOS) were analyzed semiquantitatively by immunohistochemistry.Results. ESWA provoked a significant and persistent increase of functional capillary density (FCD) throughout the observation period, reaching a maximum (140% ± 5% of BL, P < 0.05 versus sham) after 1 d when animals were treated with 1000 pulses. ESWA induced a slight increase of ...

In the present study, we aimed to evaluate whether erythropoietin (EPO) treatment may exert nonhematopoietic endothelial protection against TNF-[alpha]-induced microvascular inflammation and to determine the involvement of the nitric oxide (NO)-producing enzyme isoforms endothelial NO synthase (eNOS) and inducible NO synthase (iNOS). Murine dorsal skinfold chambers of wild-type (WT) animals were topically stimulated with TNF-[alpha] after pretreatment with epoetin beta (1,000 IU/kg body weight i.p.) or physiological saline. Leukocyte behavior, microvascular perfusion, and apoptosis were assessed by in vivo fluorescence microscopy. To study the involvement of NO, we compared eNOS-deficient (eNOS-/-) and iNOS-deficient (iNOS-/-) mice with WT animals. TNF-[alpha]-associated leukocyte activation, perfusion failure, and apoptosis were substantially attenuated in EPO-pretreated WT mice, which was accompanied by marked reduction of perivascular infiltration with F4/80-stained macrophages. The anti-inflammatory protective effects of EPO were abolished in eNOS-/-, but not in iNOS-/- mice, both with unaffected intercellular adhesion molecule 1 expression. However, the antiapoptotic effect of EPO was maintained in both eNOS-/- and iNOS-/- mice, indicating that this mechanism might rather be independent of NO. We conclude that EPO treatment elicits protection against TNF-[alpha]-induced microcirculatory dysfunction, depending on NO derived from endothelial cells, but not on the inducible isoform.

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