Impaired potency of bone marrow mononuclear cells for inducing therapeutic angiogenesis in obese diabetic rats

Department of Medical Bioregulation, Division of Cardiovascular Surgery, Yamaguchi University School of Medicine, Yamaguchi, Japan Submitted 19 July 2005 ; accepted in final form 10 October 2005 Using Zucker fatty rats, a strain characterized by diabetes and hyperlipidemia, we investigated the diabetes- and hyperlipidemia-related impairment of bone marrow mononuclear cells (BMCs) for inducing therapeutic angiogenesis. BMCs from Zucker fatty and normal Zucker lean rats were collected and cultured. Although the characterization and cell survival of BMCs did not differ, the VEGF production, endothelial differentiation, and endothelial cell colony-forming potential of BMCs from Zucker fatty rats were significantly lower than those of BMCs from lean rats. By using an ischemic hindlimb model, we found that the native recovery of induced limb ischemia in the Zucker fatty rats was also significantly worse than that in the lean rats. Furthermore, the expression of 5-hydroxytryptamine (5-HT 2A ) receptors was obviously higher in the Zucker fatty rats than that in the lean rats and was enhanced after limb ischemia. Although the therapeutic potency was lower than with the implantation of BMCs from normal lean rats, the implantation of BMCs from fatty rats could also induce angiogenesis and increase blood flow significantly in the ischemic hindlimbs of Zucker fatty rats. Furthermore, the blood flow in the ischemic hindlimbs was increased by the administration of sarpogrelate, a selective 5-HT 2A -receptor antagonist. Our results clearly show diabetes- and hyperlipidemia-related dysfunction and impaired potency for inducing angiogenesis of BMCs. However, the implantation of autologous BMCs into ischemic limbs of diabetic and hyperlipidemic rats has induced therapeutic angiogenesis effectively, and blood flow would be enhanced by the administration of a 5-HT 2A -receptor antagonist. diabetes; ischemia; blood flow; hyperlipidemia; 5-HT 2A -receptor Address for reprint requests and other correspondence: T.-S. Li, Dept. of Medical Bioregulation, Division of Cardiovascular Surgery, Yamaguchi Univ. School of Medicine, 1–1-1 Minami-Kogushi, Ube, Yamaguchi 755–8505, Japan (e-mail: litaoshe{at}yamaguchi-u.ac.jp )