Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells
Risa Ramadhiani,
Koji Ikeda,
Kazuya Miyagawa,
Gusty Rizky Tough Ryanto,
Naoki Tamada,
Yoko Suzuki,
Yuhei Kirita,
Satoaki Matoba,
Ken-ichi Hirata,
Noriaki Emoto
Affiliations
Risa Ramadhiani
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan
Koji Ikeda
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Department of Epidemiology for Longevity and Regional Health, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, Japan; Department of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, Japan; Corresponding author
Kazuya Miyagawa
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan
Gusty Rizky Tough Ryanto
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan
Naoki Tamada
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan
Yoko Suzuki
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan
Yuhei Kirita
Department of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, Japan
Satoaki Matoba
Department of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, Japan
Ken-ichi Hirata
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan
Noriaki Emoto
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan; Corresponding author
Summary: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.
