Thromboxane A synthase enhances blood flow recovery from hindlimb ischemia

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• 作者：Hideki Amano ; MD ; PhD^a ; Masaki Nakamura ; MD ; PhD^b ; Yoshiya Ito ; MD ; PhD^c ; Hiroki Kakutani ; PhD^b ; Koji Eshima ; PhD^d ; Hidero Kitasato ; PhD^b ; Shuh Narumiya ; MD ; PhD^e ; Masataka Majima ; MD ; PhD^a ; ^{mmajima@med.kitasato-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Thromboxane A synthase ; Angiogenesis ; Platelet activation ; P-selectin ligand protein-1 ; Thromboxane A2
• 刊名：Journal of Surgical Research
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：204
• 期：1
• 页码：153-163
• 全文大小：1266 K

文摘

Thromboxane A synthase (TXAS) is the enzyme that converts the arachidonic acid derivative prostaglandin H₂ to thromboxane A₂ (TXA₂). TXA₂ induces platelet aggregation, vasoconstriction, and proliferation. TXAS and TXA₂ receptors or thromboxane prostanoid (TP) receptors are elevated in numerous cardiovascular and inflammatory diseases. Platelets contain numerous angiogenesis stimulating factors. However, the involvement of TXAS on recovery from an ischemic condition is not well understood. We hypothesized that the TXAS–TXA₂–TP receptor axis would induce blood flow recovery by platelet activation.

Material and methods

The model of hindlimb ischemia was made by the right femoral artery ligation. The blood flow was estimated by laser Doppler images. Angiogenesis was estimated by the plasma level of the vascular endothelial growth factor and the stromal cell-derived factor-1 and by immunofluorescence analysis against CD31 and P-selectin glycoprotein ligand-1 (PSGL-1).

Results

In wild-type mice, blood flow recovery was enhanced by treatment with murine TXAS-overexpressing fibroblasts (C57-mTXAS) compared with empty vector- (EV) treated fibroblasts (C57-EV). Compared with C57-EV-treated mice, activated platelets (P-selectin⁺ platelets) and plasma levels of vascular endothelial growth factor and stromal cell-derived factor-1 were increased in C57-mTXAS-treated mice. The enhanced-blood flow recovery by C57-mTXAS treatment was suppressed in the TP knockout mice (TP^−/−). The expression of PSGL-1 in endothelial cells around the ischemic area was enhanced by C57-mTXAS treatment in wild-type but not in TP^−/−.

Conclusions

These results indicated that local administration of C57-mTXAS-induced angiogenesis by activated platelets that bind to PSGL-1 on ischemic endothelial cells.