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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-ERAMP2-/-) mice to clarify the contribution made by the endogenous AM-RAMP2 system to angiogenesis and metastasis. Methods and results: 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-ERAMP2-/- mice showed enhanced vascular permeability, endothelial-mesenchymal transition (EndMT)-like change, and systemic oedema. With in 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. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the function of the vascular endothelial adrenomedullin (AM)-receptor activity-modifying protein 2 (RAMP2) in the organ homeostasis and vascular integrity. It states that RAMP2 mice were crossed breed with mice expressing tamoxifen-inducible Cre-recombinase (Cre-ERT2) to create RAMP2 conditional knockout (KO) mice. Results shows that the AM-RAMP2 system is the key factor of homeostasis and vascular integrity from prenatal levels through adulthood.