Hideki Amano1, Yoshiya Ito2, Koji Eshima3, Shintaro Kato4, Fumihiro Ogawa1, Kanako Hosono1, Kazuhito Oba1, Hideaki Tamaki5, Hiroyuki Sakagami5, Masabumi Shibuya6, Shuh Narumiya7, Masataka Majima8. 1. Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan. 2. Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan. 3. Department of Immunology, Kitasato University School of Medicine, Kanagawa, Japan. 4. Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan Department of Cardiology, Kitasato University School of Medicine, Kanagawa, Japan. 5. Department of Anatomy, Kitasato University School of Medicine, Kanagawa, Japan. 6. Gakubunkan Institute of Physiology and Medicine, Jobu University, Gunma, Japan. 7. Innovation Center for Immunoregulation Technologies and Drugs (AK Project), Kyoto University Graduate School of Medicine, Kyoto City, Kyoto, Japan. 8. Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan mmajima@med.kitasto-u.ac.jp.
Abstract
AIMS: Thromboxane A2 (TXA2) 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 TXA2 receptor antagonist (S-1452) and the TXA2 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Thromboxane A2 (TXA2) 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 TXA2 receptor antagonist (S-1452) and the TXA2 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Alessandro Matte; Antonio Recchiuti; Enrica Federti; Bérengère Koehl; Thomas Mintz; Wassim El Nemer; Pierre-Louis Tharaux; Valentine Brousse; Immacolata Andolfo; Alessia Lamolinara; Olga Weinberg; Angela Siciliano; Paul C Norris; Ian R Riley; Achille Iolascon; Charles N Serhan; Carlo Brugnara; Lucia De Franceschi Journal: Blood Date: 2018-11-07 Impact factor: 22.113
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