Adrenomedullin Enhances Angiogenic Potency of Bone Marrow Transplantation in a Rat Model of Hindlimb Ischemia

Igarashi, Takashi; Nagaya, Noritoshi; Fujii, Takafumi; Itoh, Takefumi; Ishibashi‐Ueda, Hatsue; Yamagishi, Masakazu; Miyatake, Kunio; Matsumoto, Toshio; Kitamura, Soichiro; Kangawa, Kenji

doi:10.1161/01.cir.0000153352.29335.b9

Cited by 76 publications

(65 citation statements)

References 30 publications

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“…37 Recently, AM was reported to enhance angiogenic potency of bone marrow cell transplantation. 38 AM should be a novel potent candidate for an endogenous ligand for EC differentiation as well as arterial EC induction.…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors

Yurugi-Kobayashi

Itoh

Schroeder

et al. 2006

ATVB

106

122

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Objective— The acquisition of arterial or venous identity is highlighted in vascular development. Previously, we have reported an embryonic stem (ES) cell differentiation system that exhibits early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. In this study, we constructively induced differentiation of arterial and venous endothelial cells (ECs) in vitro to elucidate molecular mechanisms of arterial-venous specification. Methods and Results— ECs were induced from VEGFR2 + progenitor cells with various conditions. VEGF was essential to induce ECs. Addition of 8bromo-cAMP or adrenomedullin (AM), an endogenous ligand-elevating cAMP, enhanced VEGF-induced EC differentiation. Whereas VEGF alone mainly induced venous ECs, 8bromo-cAMP (or AM) with VEGF supported substantial induction of arterial ECs. Stimulation of cAMP pathway induced Notch signal activation in ECs. The arterializing effect of VEGF and cAMP was abolished in recombination recognition sequence binding protein at the Jκ site deficient ES cells lacking Notch signal activation or in ES cells treated with γ-secretase inhibitor. Nevertheless, forced Notch activation by the constitutively active Notch1 alone did not induce arterial ECs. Conclusions— Adrenomedullin/cAMP is a novel signaling pathway to activate Notch signaling in differentiating ECs. Coordinated signaling of VEGF, Notch, and cAMP is required to induce arterial ECs from vascular progenitors.

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Section: Discussionmentioning

confidence: 99%

Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors

Yurugi-Kobayashi

Itoh

Schroeder

et al. 2006

ATVB

106

122

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“…Angiogenesis after transplantation of bone marrow-derived mononuclear cells was augmented by AM in rats with hind limb ischemia. 84 Similarly in a rat model of cerebral infarction, the angiogenic effect of transplanted mesenchymal stem cells was enhanced by AM infusion in ischemic penumbra of the brain, improving neurological deficits. 85 Collectively, it seems likely that AM possesses angiogenic properties, suggesting its potential as a therapeutic tool in the treatment of organ or tissue ischemia.…”

Section: Angiogenetic Effect Of Ammentioning

confidence: 97%

Adrenomedullin

Kato

Tsuruda

Kita

et al. 2005

ATVB

145

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Abstract-Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Key Words: adrenomedullin Ⅲ vasodilatation Ⅲ endothelium Ⅲ smooth muscle cell Ⅲ arteriosclerosis C ardiovascular diseases secondary to arteriosclerosis of blood vessels are currently among the leading causes of death in developed countries. A number of factors, both humoral and mechanical, have been shown to modulate vascular function in humans as well as in experimental animals. 1 Blood vessel dysfunction resulting from an imbalance of those factors accelerates the process of vascular remodeling and atherosclerosis. 1 Vasoconstrictors including angiotensin II and endothelins not always but mostly act as proatherogenic factors, whereas vasodilators, either peptides or non-peptides, such as natriuretic peptides, nitric oxide (NO), and prostaglandin (PG) I 2 , have antiatherogenic properties. 1 In 1993, a new vasodilator peptide, adrenomedullin (AM), was isolated from the tissue extract of a human pheochromocytoma by monitoring cAMP levels in rat platelets. 2 Substantial levels of the AM peptide and gene expression were detected in the cardiovascular tissues including blood vessels. As listed in the Table, AM was found to exert a wide range of biological actions related to vascular functions in cultured cells, with which observations in vivo have been mostly accordant. Ever since the discovery of AM, efforts have been made to clarify the role of this bioactive peptide in blood vessels and a substantial amount of basic and clinical data has been accumulated. In this review, after summarizing the biochemical and pharmacological features of AM, we discuss its role in blood vessels, which is assumed to be protective, or inhibitory against the progression of vascular damage and remodeling. Biochemistry of AMHuman AM is a 52-aa peptide with a ring structure formed by a disulfide bond and amidated tyrosine at the C terminus ( Figure 1), both essential for binding to receptors and biological activity. 2-4 Based on sequence homology, AM is thought to belong to the calcitonin gene-related peptide (CGRP) superfamily. [2][3][4] Cloning of the cDNA encoding AM revealed the AM precursor peptide preproAM to comprise 185 amino acids, with the C terminus followed by a pair of basic amino acids, Arg-Arg, a typical processing signal (...

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“…17 Heterozygotic AM KO (AM +/− ) mice grow to adulthood with no apparent deficits but show accelerated cardiac hypertrophy, fibrosis, renal failure, and arteriosclerosis on cardiovascular injury. Given these observations, the clinical application of AM has been much anticipated [18][19][20][21][22] ; however, AM is a peptide with a short half-life in the bloodstream, which limits its usefulness for the treatment of chronic diseases.…”

Section: Clinical Perspective On P 853mentioning

confidence: 99%

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

et al. 2013

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Background-Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly. Methods and Results-We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2 −/− and E-AM−/− mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2 −/− mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2 −/− mice (DI-E-RAMP2 −/− ) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion. Conclusions -Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage. (Circulation. 2013;127:842-853.)

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Adrenomedullin Enhances Angiogenic Potency of Bone Marrow Transplantation in a Rat Model of Hindlimb Ischemia

Cited by 76 publications

References 30 publications

Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors

Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors

Adrenomedullin

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

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