title: Therapeutic ultrasound reverses peripheral ischemia in type 2 diabetic mice through PI3K-Akt-eNOS pathway.
abstract: Therapeutic ultrasound (TUS) has been demonstrated to improve endothelial nitric oxide synthase (eNOS) activity, which played a crucial role in the regulation of angiogenesis. Diabetes Mellitus (DM) impairs eNOS activity. We tested the hypothesis that DM may retard unilateral hindlimb ischemia-induced angiogenesis by inhibiting eNOS in high-fat diet (HFD)/streptozocin (STZ) induced diabetic mice, and that TUS may reverse DM-related impairment of angiogenesis. C57BL/6 mice were allocated to four groups: (A) mice were fed standard diet (control); (B) mice were fed standard diet and treated with TUS (control+TUS); (C) type-2 DM mice were induced by HFD/STZ (diabetic); and (D) type-2 DM mice and treated with TUS (dabetic+TUS). All mice were surgically induced unilateral limb ischemia. The ischemic skeletal muscles in groups B and D were irradiated with extracorporeal TUS for 9 minutes/day (frequency of 1 MHz, intensity of 0.3 W/cm2) for 14 consecutive days. The result showed that TUS augmented the blood perfusion, increased capillary density accompanied by an upregulation of angiogenic factors and a downregulation of apoptotic proteins in group D relative to group C.In vitro, TUS inhibited the apoptosis, promoted tubule formation, proliferation and migration capacities, increased angiogenic factors expression and reduced apoptotic protein levels in human umbilical vein endothelial cells (HUVECs). Furthermore, TUS can robust reverse the inhibiting effect induced by high glucose (HG) on HUVECs, and these benefits could be blocked by phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) or eNOS inhibitor (L-NAME). Together, TUS restored type-2 DM-mediated inhibition of ischemia-induced angiogenesis, partially via PI3K-Akt-eNOS signal pathway.
authors.affiliation: Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of MedicineKongjiang Road 1665, Shanghai 200092, China; Department of Vascular Surgery, Ren Ji Hospital, Shanghai Jiaotong University School of MedicineDongfang Road 1630, Shanghai 200127, China.
authors.forename: Zhao-Yang
authors.initials: ZY
authors.lastname: Lu
authors.affiliation: Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of MedicineKongjiang Road 1665, Shanghai 200092, China; Department of Vascular Surgery, Ren Ji Hospital, Shanghai Jiaotong University School of MedicineDongfang Road 1630, Shanghai 200127, China.
authors.forename: Rui-Lin
authors.initials: RL
authors.lastname: Li
authors.affiliation: Shanghai Acoustics Laboratory, Chinese Academy of Science Xiaomuqiao Road 456, Shanghai 200032, China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University Huaihai Xi Road 241, Xuhui District, Shanghai 200030, China.
authors.forename: Jing-Juan
authors.initials: JJ
authors.lastname: Huang
authors.affiliation: Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine Kongjiang Road 1665, Shanghai 200092, China.
authors.forename: Zhi-Xiao
authors.initials: ZX
authors.lastname: Su
authors.affiliation: Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine Kongjiang Road 1665, Shanghai 200092, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine Dongfang Road 1630, Shanghai 200127, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Iowa Carve College of Medicine 2000 Medical Laboratories 25 South Grand Avenue, Iowa City, IA 52242, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Nephrology Zhongshan Hospital, Fudan University Fenglin Road 180, Shanghai 200032, China.
authors.forename: Yi-Qin
authors.initials: YQ
authors.lastname: Shi
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine Dongfang Road 1630, Shanghai 200127, China.
authors.forename: Chang-Ning
authors.initials: CN
authors.lastname: Hao
authors.affiliation: Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine Kongjiang Road 1665, Shanghai 200092, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Duan
keywords: Angiogenesis; diabetic mice; hindlimb ischemia; therapeutic ultrasound