Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice.
Erythropoietin (EPO) has been proposed as a novel cytoprotectant in ischemia-reperfusion (I/R) injury of the brain, heart, and kidney. However, whether EPO exerts its protection by prevention of postischemic microcirculatory deterioration is unknown. We have investigated the effect of EPO on I/R-induced microcirculatory dysfunctions. We used the mouse dorsal skinfold chamber preparation to study nutritive microcirculation and leukocyte-endothelial cell interaction in striated muscle of the dorsal skinfold by in vivo fluorescence microscopy before 3 h of ischemia and during 5 days of reperfusion. Animals were pretreated with EPO (5,000 U/kg body wt) 1 or 24 h before ischemia. Vehicle-treated I/R-injured animals served as controls. Additional animals underwent sham operation only or were pretreated with EPO but not subjected to I/R. I/R significantly (P < 0.05) reduced functional capillary density, increased microvascular permeability, and enhanced venular leukocyte-endothelial cell interaction during early reperfusion. These findings were associated with pronounced (P < 0.05) arteriolar constriction and diminution of blood flow during late reperfusion. Pretreatment with EPO induced EPO receptor and endothelial nitric oxide synthase expression at 6 h of reperfusion (P < 0.05). In parallel, EPO significantly (P < 0.05) reduced capillary perfusion failure and microvascular hyperpermeability during early reperfusion and arteriolar constriction and flow during late reperfusion. EPO pretreatment substantially (P < 0.05) diminished I/R-induced leukocytic inflammation by reducing the number of rolling and firmly adhering leukocytes in postcapillary venules. EPO applied 1 h before ischemia induced angiogenic budding and sprouting at 1 and 3 days of reperfusion and formation of new capillary networks at 5 days of reperfusion. Thus our study demonstrates for the first time that EPO effectively attenuates I/R injury by preserving nutritive perfusion, reducing leukocytic inflammation, and inducing new vessel formation.
Contaldo
Claudio
C
Institute for Clinical and Experimental Surgery, University of Saarland, Hamburg/Saar, Germany. claudio.contaldo@usz.ch
Meier
Christoph
C
Elsherbiny
Ahmed
A
Harder
Yves
Y
Trentz
Otmar
O
Menger
Michael D
MD
Wanner
Guido A
GA
D000818:Animals; D001415:Back; D001783:Blood Flow Velocity / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D012867:Skin
D011994:Recombinant Proteins; D004921:Erythropoietin