PMID- 23045959
OWN - NLM
STAT- MEDLINE
DCOM- 20130930
LR  - 20130121
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Linking)
VI  - 12
IP  - 1
DP  - 2013 Feb
TI  - Adipose stromal cell and sarpogrelate orchestrate the recovery of 
      inflammation-induced angiogenesis in aged hindlimb ischemic mice.
PG  - 32-41
LID - 10.1111/acel.12014 [doi]
AB  - Aging population displays a much higher risk of peripheral arterial disease (PAD) 
      possibly due to the higher susceptibility, poor prognosis, and fewer therapeutic 
      options. This study was designed to examine the impact of combined multipotent 
      adipose-derived stromal cells (mADSCs) and sarpogrelate treatment on aging 
      hindlimb ischemia and the mechanism of action involved. mADSCs (1.0 x 10(7)) 
      constitutively expressing enhanced green fluorescent protein (eGFP) or firefly 
      luciferase (Fluc) reporter were engrafted into the hindlimb of aged Vegfr2-luc 
      transgenic or FVB/N mice subjected to unilateral femoral artery occlusion, 
      followed by a further administration of sarpogrelate. Multimodality molecular 
      imaging was employed to noninvasively evaluate mADSCs' survival and therapeutic 
      efficacy against aging hindlimb ischemia. Aged Tg(Vegfr2-luc) mice exhibited 
      decreased inflammatory response, and downregulation of vascular endothelial 
      growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) 
      compared with young ones following hindlimb ischemia induction, resulting in 
      angiogenesis insufficiency and decompensation for ischemia recovery. Engrafted 
      mADSCs augmented inflammation-induced angiogenesis to yield 
      pro-angiogenic/anti-apoptotic effects partly via the VEGF/VEGFR2/mTOR/STAT3 
      pathway. Nonetheless, mADSCs displayed limited survival and efficacy following 
      transplantation. Sarpogrelate treatment with mADSCs further upregulated mammalian 
      target of rapamycin (mTOR)/STAT3 signal and modulated pro-/anti-inflammatory 
      markers including IL-1beta/TNF-alpha/IFN-gamma and IL-6/IL-10, which ultimately facilitated 
      mADSCs' survival and therapeutic benefit in vivo. Sarpogrelate prevented mADSCs 
      from hypoxia/reoxygenation-induced cell death via a mTOR/STAT3-dependent pathway 
      in vitro. This study demonstrated a role of in vivo kinetics of VEGFR2 as a 
      biomarker to evaluate cell-derived therapeutic angiogenesis in aging. mADSCs and 
      sarpogrelate synergistically restored impaired angiogenesis and inflammation 
      modulatory capacity in aged hindlimb ischemic mice, indicating its therapeutic 
      promise for PAD in the elderly.
CI  - (c) 2012 The Authors Aging Cell (c) 2012 Blackwell Publishing Ltd/Anatomical Society 
      of Great Britain and Ireland.
FAU - Fan, Weiwei
AU  - Fan W
AD  - Department of Cardiology & Molecular Imaging Program, Xijing Hospital, Fourth 
      Military Medical University, Xi'an, Shaanxi, 710032, China.
FAU - Li, Chengxiang
AU  - Li C
FAU - Qin, Xing
AU  - Qin X
FAU - Wang, Shenxu
AU  - Wang S
FAU - Da, Hu
AU  - Da H
FAU - Cheng, Kang
AU  - Cheng K
FAU - Zhou, Ri
AU  - Zhou R
FAU - Tong, Chao
AU  - Tong C
FAU - Li, Xiujuan
AU  - Li X
FAU - Bu, Qingting
AU  - Bu Q
FAU - Li, Congye
AU  - Li C
FAU - Han, Yaling
AU  - Han Y
FAU - Ren, Jun
AU  - Ren J
FAU - Cao, Feng
AU  - Cao F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121121
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Succinates)
RN  - 19P708E787 (sarpogrelate)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
SB  - IM
MH  - Adipose Tissue/*cytology/metabolism
MH  - Aging/metabolism/*pathology
MH  - Angiogenesis Inducing Agents/pharmacology
MH  - Animals
MH  - Disease Models, Animal
MH  - Hindlimb/*blood supply/metabolism
MH  - Inflammation/drug therapy/metabolism/*pathology
MH  - Ischemia/drug therapy/metabolism/pathology/*therapy
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Neovascularization, Physiologic/drug effects/physiology
MH  - Platelet Aggregation Inhibitors/pharmacology
MH  - Signal Transduction
MH  - Stromal Cells/cytology/metabolism/*transplantation
MH  - Succinates/*pharmacology
MH  - Vascular Endothelial Growth Factor Receptor-2/biosynthesis
EDAT- 2012/10/11 06:00
MHDA- 2013/10/01 06:00
CRDT- 2012/10/11 06:00
PHST- 2012/09/30 00:00 [accepted]
PHST- 2012/10/11 06:00 [entrez]
PHST- 2012/10/11 06:00 [pubmed]
PHST- 2013/10/01 06:00 [medline]
AID - 10.1111/acel.12014 [doi]
PST - ppublish
SO  - Aging Cell. 2013 Feb;12(1):32-41. doi: 10.1111/acel.12014. Epub 2012 Nov 21.