Adiponectin-mediated modulation of lymphatic vessel formation and lymphedema.
BACKGROUND
Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down-regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms.


RESULTS
A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin-knockout mice showed the greater diameter of the injured tail compared with wild-type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild-type and adiponectin-knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP-activated protein kinase (AMPK), Akt, and endothelial nitric oxide synthase n LECs. Blockade of AMPK or Akt activity abolished adiponectin-stimulated increase in LEC differentiation and viability and endothelial nitric oxide synthase phosphorylation. Inhibition of AMPK activation also suppressed adiponectin-induced Akt phosphorylation in LECs. In contrast, inactivation of Akt signaling had no effects on adiponectin-mediated AMPK phosphorylation in LECs. Furthermore, adiponectin administration did not affect the thickening of the damaged tail in endothelial nitric oxide synthase-knockout mice.


CONCLUSIONS
Adiponectin can promote lymphatic vessel formation via activation of AMPK/Akt/endothelial nitric oxide synthase signaling within LECs, thereby leading to amelioration of lymphedema.
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yuuki
Y
Shimizu
Rei
R
Shibata
Masakazu
M
Ishii
Koji
K
Ohashi
Takahiro
T
Kambara
Yusuke
Y
Uemura
Daisuke
D
Yuasa
Yoshiyuki
Y
Kataoka
Shinji
S
Kihara
Toyoaki
T
Murohara
Noriyuki
N
Ouchi
D052242:Adiponectin / Q000502:physiology*; D000818:Animals; D042783:Endothelial Cells / Q000502:physiology; D042583:Lymphangiogenesis; D008209:Lymphedema / Q000209:etiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
D052242:Adiponectin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
AMPK; Akt; adiponectin; eNOS; lymphangiogenesis