The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis.
Cardiovasc Res
; 111(4): 398-409, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27307317
ABSTRACT
AIMS:
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. METHODS ANDRESULTS:
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.CONCLUSION:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Movimento Celular
/
Células Endoteliais
/
Adrenomedulina
/
Proteína 2 Modificadora da Atividade de Receptores
/
Homeostase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Japão