Sustained release of erythropoietin using biodegradable gelatin hydrogel microspheres persistently improves lower leg ischemia.
OBJECTIVE
We hypothesized that erythropoietin (EPO)-immersed gelatin hydrogel microspheres (GHM) injected into ischemic legs might continuously release a small amount of EPO to locally stimulate angiogenesis without unfavorable systemic effects.


BACKGROUND
EPO is a potent angiogenic factor, but its use for relieving ischemic organs is limited because of the untoward systemic erythrogenic effect and its short half-life in plasma.


METHODS
The right femoral arteries of BALB/c mice were ligated. Recombinant human EPO (5,000 IU/kg)-immersed GHM was injected into the right hind limb muscles (n = 12); the control groups included a saline-injected group (n = 12), an EPO-injected group (n = 8), and an empty GHM-injected group (n = 8).


RESULTS
Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the EPO-GHM group compared with any of the control groups. There was no increase in the hemoglobin level, nor was there any increase in endothelial progenitor cells. However, capillary and arteriolar densities were significantly increased in this group. Although the treatment did not affect the levels of vascular endothelial growth factor or interleukin-1 beta, it up-regulated the EPO receptor and matrix metalloproteinase-2 and activated the downstream signaling of Akt and also endothelial nitric oxide synthase in ischemic limbs, which might have been associated with the evident angiogenic and arteriogenic effects in the present system.


CONCLUSIONS
The present drug delivery system is suggested to have potential as a novel noninvasive therapy for ischemic peripheral artery disease.
Li
Longhu
L
Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Okada
Hideshi
H
Takemura
Genzou
G
Esaki
Masayasu
M
Kobayashi
Hiroyuki
H
Kanamori
Hiromitsu
H
Kawamura
Itta
I
Maruyama
Rumi
R
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
Tabata
Yasuhiko
Y
Minatoguchi
Shinya
S
D053687:Adult Stem Cells / Q000187:drug effects; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003692:Delayed-Action Preparations; D042783:Endothelial Cells / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage*; D020100:Hydrogels / Q000627:therapeutic use; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D012039:Regional Blood Flow / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D003692:Delayed-Action Preparations; D020100:Hydrogels; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin