The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis

Tanaka, Megumu; Koyama, Teruhide; Sakurai, Takayuki; Kamiyoshi, Akiko; Ichikawa-Shindo, Yuka; Kawate, Hisaka; Liu, Tian; Xian, Xian; Imai, Atsushi; Zhai, Ling; Hirabayashi, Kei; Owa, Shinji; Yamauchi, Akira; Igarashi, Kyoko; Taniguchi, Shun’ichiro; Shindo, Takayuki

doi:10.1093/cvr/cvw166

Cited by 46 publications

(44 citation statements)

References 37 publications

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“…A constitutive flow-dependent autocrine or paracrine mechanism is also indicated by our observation of strong defects in fluid shear stress-induced cellular effects in isolated endothelial cells with suppressed adrenomedullin and adrenomedullin receptor expression as well as in flow-induced vasodilation in vessels isolated from endothelium-specific CALCRL-and adrenomedullin-deficient mice. Flow-induced adrenomedullin-dependent cAMP production and eNOS activation may also be critically involved in other adrenomedullin functions that have been shown to require endothelial adrenomedullin release and functional endothelial adrenomedullin receptors, such as angiogenesis and maintenance of endothelial barrier function (61)(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Iring

Jin

Albarrán-Juárez

et al. 2019

Journal of Clinical Investigation

153

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Section: Discussionmentioning

confidence: 99%

Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Iring

Jin

Albarrán-Juárez

et al. 2019

Journal of Clinical Investigation

153

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“…However, since these genes are not endothelial-specific, the contribution of these genes in endothelial cells to pre-metastatic niche formation still remains unclear. A recent study demonstrated that endothelial cell-specific overexpression of receptor activity modifying protein 2 (RAMP2), a receptor for a hormone adrenomedullin, improves vascular integrity and is protective against metastasis of sarcoma and melanoma in mice [ 35 ]. We also previously showed that ANP inhibits LPS-induced inflammation through down-regulation of E-selectin, resulting in reduced metastasis of melanoma cells [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche formation by solid cancers

et al. 2017

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Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied in vivo. On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche.

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“…Also the role of the ADM–RAMP 2 system has been investigated. Mice lacking the gene encoding for RAMP 2 showed enhanced vascular permeability and systemic oedema . Similarly, mice with a conditional knock‐out of ADM in endothelial cells revealed increased vascular permeability in comparison with wild‐type littermates …”

Section: Vascular Effects Of Adrenomedullinmentioning

confidence: 96%

“…Mice lacking the gene encoding for RAMP 2 showed enhanced vascular permeability and systemic oedema. 36 Similarly, mice with a conditional knock-out of ADM in endothelial cells revealed increased vascular permeability in comparison with wild-type littermates. 39 Further support for the effects of ADM in maintaining vascular integrity comes from experimental studies showing that experimental overexpression of ADM inhibits systemic and pulmonary vascular leakage in animals.…”

Section: Vascular Effects Of Adrenomedullinmentioning

confidence: 98%

“…This is most likely the consequence of a counteracting response, as the ADM‐induced stabilization of endothelial barrier function is thought to limit tissue fluid overload. Indeed, disruption of the ADM system results in vascular leakage and systemic and pulmonary oedema . Also the role of the ADM–RAMP 2 system has been investigated.…”

Section: Vascular Effects Of Adrenomedullinmentioning

confidence: 99%

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Adrenomedullin in heart failure: pathophysiology and therapeutic application

Voors

Kremer

Geven

et al. 2018

European J of Heart Fail

177

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Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin–angiotensin–aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio‐ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio‐ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non‐neutralizing ADM‐binding antibody with a half‐life of 15 days. Adrecizumab binds at the N‐terminal epitope of ADM, leaving the C‐terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM‐binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

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The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis

Cited by 46 publications

References 37 publications

Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche formation by solid cancers

Adrenomedullin in heart failure: pathophysiology and therapeutic application

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