The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis.
Controlling vascular integrity is expected to be a novel therapeutic target of cancers as well as cardiovascular diseases. Adrenomedullin (AM) and its receptor-modulating protein, RAMP2, have been identified as essential mediators of cardiovascular homeostasis. In this study, we used inducible vascular endothelial cell-specific RAMP2 knockout (DI-E-RAMP2(-/-)) mice to clarify the contribution made by the endogenous AM-RAMP2 system to angiogenesis and metastasis.



Subcutaneously transplanted sarcoma or melanoma cells showed less growth and angiogenesis in DI-E-RAMP2(-/-) than in control mice. On the other hand, after the transplantation of B16BL6 melanoma cells into hindlimb footpads, spontaneous metastasis to the lung was enhanced in DI-E-RAMP2(-/-) mice. Early after RAMP2 gene deletion, DI-E-RAMP2(-/-) mice showed enhanced vascular permeability, endothelial-mesenchymal transition (EndMT)-like change, and systemic oedema. Within the lungs of DI-E-RAMP2(-/-) mice, pulmonary endothelial cells were deformed, and inflammatory cells infiltrated the vessel walls and expressed the chemotactic factors S100A8/9 and SAA3, which attract tumour cells and mediate the formation of a pre-metastatic niche. Conversely, the overexpression of RAMP2 suppressed tumour cell adhesion to endothelial cells, tumour metastasis, and improved survival.



These findings indicate that the AM-RAMP2 system regulates vascular integrity, whereas RAMP2 deletion promotes vascular permeability and EndMT-like change within primary lesions and formation of pre-metastatic niches in distant organs by destabilizing the vascular structure and inducing inflammation. Vascular integrity regulated by the AM-RAMP2 system could thus be a hopeful therapeutic target for suppressing tumour metastasis.
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Megumu
M
Tanaka
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Teruhide
T
Koyama
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Takayuki
T
Sakurai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Akiko
A
Kamiyoshi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Yuka
Y
Ichikawa-Shindo
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Hisaka
H
Kawate
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Tian
T
Liu
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Xian
X
Xian
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Akira
A
Imai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Liuyu
L
Zhai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Kazutaka
K
Hirabayashi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Shinji
S
Owa
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Akihiro
A
Yamauchi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Kyoko
K
Igarashi
Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Shun'ichiro
S
Taniguchi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan tshindo@shinshu-u.ac.jp.
Takayuki
T
Shindo
D053607:Adrenomedullin / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000172:deficiency / Q000378:metabolism*
C545506:Ramp2 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D053607:Adrenomedullin
Endothelial cell; Fibrosis; Inflammation; Macrophages; Vascular integrity