VEGF secretion by adipose tissue-derived regenerative cells is impaired under hyperglycemic conditions via glucose transporter activation and ROS increase.
Transplantation of cultured adipose-derived regenerative cells (ADRCs) into ischemic tissues promotes neovascularization and blood perfusion recovery. These effects are attenuated in diabetes patients. We examined the effects of hyperglycemia on the angiogenic capacity of ADRCs derived from Wistar rats both in vivo and in vitro. Cultured ADRCs were predominantly composed of CD90 positive cells; prevalence of CD90 positive cells was not affected by hyperglycemia. mRNA and protein levels of vascular endothelial growth factor (VEGF) were significantly decreased in ADRCs under hyperglycemic conditions independent of osmolarity, whereas mRNA levels of hepatocyte growth factor and fibroblast growth factor were unaffected. Since ADRCs express glucose transporter proteins GLUT1, 3 and 4, we examined the effects of the glucose transporter inhibitor phloretin on reactive oxygen species (ROS) and angiogenic factors. Phloretin decreased the glucose uptake rate, reduced ROS, and increased VEGF mRNA in ADRCs exposed to a hyperglycemic condition. In vivo transplantation of ADRCs cultured under hyperglycemic conditions into mouse ischemic limbs resulted in significantly decreased blood perfusion and capillary density in ischemic regions compared with transplantation of ADRCs cultured under normoglycemic conditions. These results suggest that hyperglycemia impaired VEGF production in ADRCs via an increase of ROS, impairing the angiogenic capacity of ADRCs transplanted into ischemic limbs.
Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science.
Hiromi
H
Matsugami
Yusuke
Y
Harada
Yasutaka
Y
Kurata
Yasutaka
Y
Yamamoto
Yuki
Y
Otsuki
Hisako
H
Yaura
Yumiko
Y
Inoue
Kumi
K
Morikawa
Akio
A
Yoshida
Yasuaki
Y
Shirayoshi
Yoshiko
Y
Suyama
Bin
B
Nakayama
Hideki
H
Iwaguro
Kazuhiro
K
Yamamoto
Ichiro
I
Hisatome
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005434:Flow Cytometry; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D051246:Glucose Transport Proteins, Facilitative; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat