Apelin induces enlarged and nonleaky blood vessels for functional recovery from ischemia

Kidoya, Hiroyasu; Naito, Hisamichi; Takakura, Nobuyuki

doi:10.1182/blood-2009-07-232306

Cited by 107 publications

(111 citation statements)

References 48 publications

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“…Overexpression of apelin greatly inhibited the growth of colon26 tumors in all three cell lines derived from distinct clones (Figure 2b). In agreement with a previous report that apelin induced enlarged blood vessels in the dermis of apelin Tg mice (Kidoya et al, 2010), the caliber of blood vessels observed in tumors formed by colon26 cells transduced with apelin was enlarged compared with control colon26 tumors (Figures 2c-e). This enlargement of tumor vessels is not dependent on tumor size, because the lumen size of the vessels was different even for tumors of the same volume (300 mm 3 ) (Supplementary Figure 1; day 8 for colon26/vector, day 10 for colon26/apelin).…”

Section: Apelin Induces Blood Vessel Enlargement In Tumors and Inhibisupporting

confidence: 81%

“…Apelin induces larger cords of ECs, mainly mediated by cell-cell aggregation, resulting in the formation of enlarged blood vessels (Kidoya et al, 2008). These enlarged blood vessels are stable, and vascular permeability was reduced (Kidoya et al, 2010). Taken together, these data support the notion that the apelin/ APJ pathway has an important role in vascular maturation, especially for regulating the caliber of blood vessels to facilitate lumen enlargement (Kasai et al, 2008;Kidoya et al, 2008).…”

Section: Introductionsupporting

confidence: 73%

“…We previously reported temporal expression of APJ in ECs during angiogenesis in embryos and during the process of recovery from ischemic states (Kidoya et al, 2008(Kidoya et al, , 2010. To determine whether apelin and APJ are expressed in a cell type-specific manner in ECs of tumor vessels, we evaluated the expression of vascular apelin and APJ in growing syngeneic mouse tumors by realtime PCR and immunohistochemical analyses.…”

Section: Apelin and Apj Are Highly Expressed In Tumor Ecsmentioning

confidence: 99%

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The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

et al. 2011

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Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported to improve the effect of immuno-, chemo-and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.

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Section: Apelin Induces Blood Vessel Enlargement In Tumors and Inhibisupporting

confidence: 81%

Section: Introductionsupporting

confidence: 73%

Section: Apelin and Apj Are Highly Expressed In Tumor Ecsmentioning

confidence: 99%

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The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

et al. 2011

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“…The pathophysiological effects of apelin in angiogenesis have also been reported for the liver, where the apelinergic system is a factor in portosystemic collaterisation and splanchnic neovascularisation in portal hypotensive rats (Tiani et al 2009) as well as in neovascularisation during liver cirrhosis (Principe et al 2008). However, apelin may have therapeutic effects in ischaemia recovery due to vessel regeneration and endothelial proliferation (Eyries et al 2008) and blood vessel diameter regulation (Kidoya et al 2010). These findings indicate that apelin is a crucial factor for angiogenesis and that there may be therapeutic potential in both the disruption of its signalling (e.g.…”

Section: Role Of Apelin/apj In Angiogenesismentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

288

216

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The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

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“…3,4 Since its discovery, the apelin-APJ system has emerged as an important regulator of cardiovascular homeostasis and may have a critical role in the pathophysiological development of cardiovascular diseases; it has also been regarded as a new therapeutic research and drug design target. [5][6][7][8][9][10][11] The functions of apelin-APJ appear to be complex and have yet to be defined by consensus. The accumulating evidences have indicated that the functions of apelin-APJ may be dependent on its target organs and its physiological/pathophysiological state.…”

Section: Introductionmentioning

confidence: 99%

Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

et al. 2011

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Apelin and its G-protein-coupled receptor APJ are potent regulators of the cardiovascular system. Recent studies have suggested that apelin-APJ reverses the function of angiotensin II (Ang II)-the Ang II type 1 receptor (AT 1 ). However, the mechanism remains unclear because of the accumulating evidences that apelin-APJ may contribute to both cardioprotection and pathological progression. In human embryonic kidney 293 cells, we found that coexpression with APJ significantly suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by Ang II-AT 1 , whereas apelin abolished this attenuation through activated APJ independently of its heterodimerization. Pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the ERK1/2 phosphorylation level similar to that found with AT 1 and APJ coexpression without apelin stimulation. In contrast, coexpression of the beta-2-adrenergic receptor or the pharmacologically non-activated Ang II type 2 receptor (AT 2 ) pretreated with the AT 2 -specific antagonist, PD123319, did not affect ERK1/2 phosphorylation through AT 1 . Pretreatment with 30 nM of the AT 1 blocker (ARB) TA-606A suppressed 50% of the AT 1 -mediated ERK1/2 phosphorylation, whereas 30 nM of TA-606A achieved 75% suppression when the non-activated APJ was coexpressed without ligand or PTX. However, 120 nM of TA-606A failed to reach the target phosphorylation when it was coexpressed with activated APJ with apelin. Based on these results, we demonstrated that non-activated APJ may suppress Ang II-AT 1 signaling, whereas this ligand-independent function was diminished with apelin activation. These results may be relevant to the potential contribution of apelin-APJ to ARB treatment in the clinical realm.

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Apelin induces enlarged and nonleaky blood vessels for functional recovery from ischemia

Cited by 107 publications

References 48 publications

The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

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