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Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice

フォーマット:
論文
責任表示:
Qia, Xun ; Okamoto, Yasuo ; Murakawa, Tomomi ; Wang, Fei ; Oyama, Osamu ; Ohkawa, Ryunosuke ; Yoshioka, Kazuaki ; Du, Wa ; Sugimoto, Naotoshi ; Yatomi, Yutaka ; Takuwa, Noriko ; Takuwa, Yoh
言語:
英語
出版情報:
Elsevier BV, 2010-05-01
著者名:
Qia, Xun
Okamoto, Yasuo
Murakawa, Tomomi
Wang, Fei
Oyama, Osamu
Ohkawa, Ryunosuke
Yoshioka, Kazuaki
Du, Wa
Sugimoto, Naotoshi
Yatomi, Yutaka
Takuwa, Noriko
Takuwa, Yoh
続きを見る
掲載情報:
European Journal of Pharmacology
ISSN:
0014-2999  CiNii Research  Webcat Plus  JAIRO
巻:
634
通号:
1-3
開始ページ:
121
終了ページ:
131
バージョン:
author
概要:
金沢大学医薬保健研究域医学系<br />Therapeutic angiogenesis is a promising strategy for treating ischemia. The lysophospholipid mediator sphingosine-1-phosphate (S1P) acts on vascular endothelial cells to stimulate migration and tube formation, and plays the critical role in developmental angiogenesis. We developed poly(lactic-co-glycolic-acid) (PLGA)-based S1P-containing microparticles (PLGA-S1P), which are biodegradable and continuously release S1P, and studied the effects of PLGA-S1P on neovascularization in murine ischemic hindlimbs. Intramuscular injections of PLGA-S1P stimulated blood flow in C57BL/6 mice dose-dependently, with repeated administrations at a 3-day interval, rather than a single bolus or 6-day interval, over 28. days conferring the optimal stimulating effect. In Balb/c mice that exhibit limb necrosis and dysfunction due to retarded blood flow recovery, injections of PLGA-S1P stimulated blood flow with alleviation of limb necrosis and dysfunction. PLGA-S1P alone did not induce edema in ischemic limbs, and rather blocked vascular endothelial growth factor-induced edema. PLGA-S1P not only increased the microvessel densities in ischemic muscle, but promoted coverage of vessels with smooth muscle cells and pericytes, thus stabilizing vessels. PLGA-S1P stimulated Akt and ERK with increased phosphorylation of endothelial nitric oxide synthase in ischemic muscle. The effects of the nitric oxide synthase inhibitor, Nω-nitro-l-arginine methylester, showed that PLGA-S1P-induced blood flow stimulation was partially dependent on nitric oxide. Injections of PLGA-S1P also increased the expression of angiogenic factors and the recruitment of CD45-, CD11b- and Gr-1-positive myeloid cells, which are implicated in post-ischemic angiogenesis, into ischemic muscle. These results indicate that PLGA-based, sustained local delivery of S1P is a potentially useful therapeutic modality for stimulating post-ischemic angiogenesis. © 2010 Elsevier B.V. 続きを見る
URL:
http://hdl.handle.net/2297/23922
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