Semaphorin3E-PlexinD1 signaling in coronary artery and lymphatic vessel development with clinical implications in myocardial recovery
Kazuaki Maruyama,
Kazuaki Naemura,
Yuichiro Arima,
Yasunobu Uchijima,
Hiroaki Nagao,
Kenji Yoshihara,
Manvendra K. Singh,
Akiyoshi Uemura,
Fumio Matsuzaki,
Yutaka Yoshida,
Yukiko Kurihara,
Sachiko Miyagawa-Tomita,
Hiroki Kurihara
Affiliations
Kazuaki Maruyama
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Isotope Science Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Corresponding author
Kazuaki Naemura
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
Yuichiro Arima
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Cardiovascular Medicine, Faculty of Life Sciences, Kumamoto University, 2-2-1 Honjo, Kumamoto, Kumamoto 860-0811, Japan
Yasunobu Uchijima
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Hiroaki Nagao
Heart Center, Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Kenji Yoshihara
Heart Center, Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Manvendra K. Singh
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, and the National Heart Research Institute Singapore, National Heart Center Singapore, 8 College Road Singapore 169857, Singapore
Akiyoshi Uemura
Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
Fumio Matsuzaki
Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, 2-2-3, Minatojiima-Minamimachi, Chuou-ku, Kobe 650-0047, Japan
Yutaka Yoshida
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
Yukiko Kurihara
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Sachiko Miyagawa-Tomita
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Heart Center, Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan; Department of Animal Nursing Science, Yamazaki University of Animal Health Technology, 4-7-2 Minami-Osawa, Hachioji, Tokyo 192-0364, Japan
Hiroki Kurihara
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Summary: Blood and lymphatic vessels surrounding the heart develop through orchestrated processes from cells of different origins. In particular, cells around the outflow tract which constitute a primordial transient vasculature, referred to as aortic subepicardial vessels, are crucial for the establishment of coronary artery stems and cardiac lymphatic vessels. Here, we revealed that the epicardium and pericardium-derived Semaphorin 3E (Sema3E) and its receptor, PlexinD1, play a role in the development of the coronary stem, as well as cardiac lymphatic vessels. In vitro analyses demonstrated that Sema3E may demarcate areas to repel PlexinD1-expressing lymphatic endothelial cells, resulting in proper coronary and lymphatic vessel formation. Furthermore, inactivation of Sema3E-PlexinD1 signaling improved the recovery of cardiac function by increasing reactive lymphangiogenesis in an adult mouse model of myocardial infarction. These findings may lead to therapeutic strategies that target Sema3E-PlexinD1 signaling in coronary artery diseases.
