Coordinated linear and rotational movements of endothelial cells compartmentalized by VE-cadherin drive angiogenic sprouting
Kazuo Tonami,
Tatsuya Hayashi,
Yasunobu Uchijima,
Masahiro Kanai,
Fumitaka Yura,
Jun Mada,
Kei Sugahara,
Yukiko Kurihara,
Yuri Kominami,
Toshiyuki Ushijima,
Naoko Takubo,
Xiaoxiao Liu,
Hideto Tozawa,
Yoshimitsu Kanai,
Tetsuji Tokihiro,
Hiroki Kurihara
Affiliations
Kazuo Tonami
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan; Corresponding author
Tatsuya Hayashi
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan; Graduate School of Mathematical Science, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8914, Japan; Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, 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
Masahiro Kanai
Department of Education and Creation Engineering, Kurume Institute of Technology, 2228-66 Kamitsu-machi, Kurume, Fukuoka 830-0052, Japan
Fumitaka Yura
Department of Complex and Intelligent Systems, School of Systems Information Science, Future University Hakodate, 116-2 Kamedanakano-cho, Hakodate, Hokkaido 041-8655, Japan
Jun Mada
College of Industrial Technology, Nihon University, 2-11-1 Shin-ei, Narashino, Chiba 275-8576, Japan
Kei Sugahara
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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
Yuri Kominami
Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-865, Japan
Toshiyuki Ushijima
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Naoko Takubo
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan; Isotope Science Center, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Xiaoxiao Liu
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Hideto Tozawa
Department of Chemistry, Graduate School of Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Yoshimitsu Kanai
Cell Biology and Anatomy, Graduate School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan
Tetsuji Tokihiro
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan; Graduate School of Mathematical Science, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8914, Japan; Department of Mathematical Engineering, Faculty of Engineering, Musashino University, 3-3-3 Ariake, Koto-ku, Tokyo 135-8181, 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; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan; Corresponding author
Summary: Angiogenesis is a sequential process to extend new blood vessels from preexisting ones by sprouting and branching. During angiogenesis, endothelial cells (ECs) exhibit inhomogeneous multicellular behaviors referred to as “cell mixing,” in which ECs repetitively exchange their relative positions, but the underlying mechanism remains elusive. Here we identified the coordinated linear and rotational movements potentiated by cell-cell contact as drivers of sprouting angiogenesis using in vitro and in silico approaches. VE-cadherin confers the coordinated linear motility that facilitated forward sprout elongation, although it is dispensable for rotational movement, which was synchronous without VE-cadherin. Mathematical modeling recapitulated the EC motility in the two-cell state and angiogenic morphogenesis with the effects of VE-cadherin-knockout. Finally, we found that VE-cadherin-dependent EC compartmentalization potentiated branch elongations, and confirmed this by mathematical simulation. Collectively, we propose a way to understand angiogenesis, based on unique EC behavioral properties that are partially dependent on VE-cadherin function.
