Journal
CARDIOVASCULAR RESEARCH
Volume 107, Issue 4, Pages 509-521Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvv139
Keywords
Platelets; Thromboxane receptor; Angiogenesis; PSGL-1; P-selectin
Categories
Funding
- High-Tech Research Center grant from the Japanese Ministry of Education, Culture, Sports, Science, and Technology
- [19790979]
- [21791331]
- [40215017]
- [21390072]
- Grants-in-Aid for Scientific Research [26430120, 15K08241] Funding Source: KAKEN
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Aims Thromboxane A(2) (TXA(2)) induces platelet adhesion through thromboxane prostanoid (TP) receptor. Platelets contain many pro-angiogenic factors and are recruited to the site of vascular injury. However, the cellular and molecular mechanisms of platelet-dependent angiogenesis, especially the involvement of TP signalling, have not been fully elucidated. The present study hypothesized that TP-dependent platelet adhesion would contribute to angiogenesis in a mouse hindlimb ischaemic model. Methods and results Blood flow recovery was suppressed by the TXA(2) receptor antagonist (S-1452) and the TXA(2) synthase inhibitor (OKY-046) compared with control mice. TP knockout mice (TP-/-) showed delayed blood flow recovery from ischaemia and impaired angiogenesis compared with wild-type (WT) mice and prostacyclin receptor knockout mice (IP-/-). Selective platelet adhesion to ischaemic endothelial cells (ECs) via P-selectin was identified in WT and IP-/-, but not in TP-/-, via in vivo microscopy. IF analysis showed that P-selectin glycoprotein ligand-1 (PSGL-1) co-localized with endothelial CD31 in ischaemic muscle in WT and IP-/- but not diminished in TP-/-. Platelet-rich plasma levels of stromal cell-derived factor-1 and VEGF were increased after ischaemia in WT, and suppressed by antibody against P-selectin in WT but not in TP-/-. Furthermore, the blood flow recovery was suppressed by neutralizing antibodies against VEGF or C-X-C chemokine receptor type 4 in WT and IP-/- but not in TP-/-. Conclusion These results indicated that TP signalling facilitates ischaemia-induced angiogenesis via P-selectin-mediated platelet adhesion to PSGL-1 on the ECs at ischaemic sites and the supply of pro-angiogenic factors by the adherent platelets.
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