Topical administration of sphingosine-1-phosphate (S1P)
stimulates ischemia-induced angiogenesis in the mouse
limb
Xun
Qi, Naotoshi Sugimoto, Noriko Takuwa, Osamu Oyama, Fei
Wang, Yoh Takuwa
Dept. Physiol., Grad. Med., Kanazawa Univ.
ABSTRACT
S1P has a critical role in vascular maturation in vivo
during mammalian development. However, little is known
about the therapeutic effect of S1P in ischemia-induced
angiogenesis in adults. We investigated the effect of
exogeneous S1P on angiogenesis in ischemic skeletal muscle
in adult mice. Unilateral murine hindlimb ischemic model is
an well-established in vivo angiogenesis assay system. We
evaluated post-ischemic angiogenesis by monitoring
post-surgical blood flow recovery with a laser doppler
imager and the capillary density with anti-CD31
immunohistochemistry. First, we injected S1P solution into
the ischemic muscle everyday during 28 days after surgery
in C57BL6/J mice. The limb blood flow was significantly
elevated between 10 and 28 days after surgery in
S1P-injected mice compared to vehicle-injected mice. The
capillary density was significantly increased in the
S1P-administered group at 10 days after surgery. Next, we
administrated several different doses of S1P into the
ischemic lesion everyday. S1P accelerated recovery of the
blood flow from ischemia and induced an increase in the
capillary density in a dose-dependent manner. Basic FGF
(bFGF) is known to be one of the most potent angiogenic
factors, daily injection of bFGF increased the blood flow
and the capillary density in the ischemic limb. The
comparison of the effects between S1P and bFGF showed that
S1P stimulated ischemia-induced angiogenesis to the similar
extent of bFGF. These results suggest the possibility that
S1P could be a potential therapeutic agent for ischemic
diseases.