Apelin Receptor Can Act as a Specific Marker and Promising Therapeutic Target for Infantile Hemangioma

Chen, Qianyi; Ying, Hanru; Zhang, Yu; Chang, Lei; Chen, Zongan; Chen, Jialin; Chang, Shih‐Jen; Qiu, Yajing; Lin, Xiaoxi

doi:10.1016/j.jid.2022.09.657

Cited by 5 publications

(5 citation statements)

References 54 publications

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“…Recently, Apelin expression was reported in ECs from infantile hemangioma (IH), a human vascular anomaly, and blockade of Apelin signaling via Aplnr/Apj antagonism suppressed angiogenic tumor formation in an IH mouse model. 39 Our data identify Rbpj as a regulator of Apelin and offer potential for pharmacological treatments for bAVM patients with perturbations to Apelin signaling.…”

Section: Discussionmentioning

confidence: 74%

Rbpj Deficiency Disrupts Vascular Remodeling via Abnormal Apelin and Cdc42 (Cell Division Cycle 42) Activity in Brain Arteriovenous Malformation

Adhicary

Fanelli

Nakisli

et al. 2023

Stroke

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BACKGROUND: Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous shunts, bypassing the artery-capillary-vein network and disrupting blood flow. Clinically, bAVM treatments are invasive and not routinely applicable. There is critical need to understand mechanisms of bAVM pathologies and develop pharmacological therapies. METHODS: We used an in vivo mouse model of Rbpj-mediated bAVM, which develops pathologies in the early postnatal period and an siRNA in vitro system to knockdown RBPJ in human brain microvascular endothelial cells (ECs). To understand molecular events regulated by endothelial Rbpj, we conducted RNA-Seq and chromatin immunoprecipitation-Seq analyses from isolated brain ECs. RESULTS: Rbpj-deficient (mutant) brain ECs acquired abnormally rounded shape (with no change to cell area), altered basement membrane dynamics, and increased endothelial cell density along arteriovenous shunts, compared to controls, suggesting impaired remodeling of neonatal brain vasculature. Consistent with impaired endothelial cell dynamics, we found increased Cdc42 (cell division cycle 42) activity in isolated mutant ECs, suggesting that Rbpj regulates small GTPase (guanosine triphosphate hydrolase)-mediated cellular functions in brain ECs. siRNA-treated, RBPJ -deficient human brain ECs displayed increased Cdc42 activity, disrupted cell polarity and focal adhesion properties, and impaired migration in vitro. RNA-Seq analysis from isolated brain ECs identified differentially expressed genes in mutants, including Apelin , which encodes a ligand for G protein-coupled receptor signaling known to influence small GTPase activity. Chromatin immunoprecipitation-Seq analysis revealed chromatin loci occupied by Rbpj in brain ECs that corresponded to G-protein and Apelin signaling molecules. In vivo administration of a competitive peptide antagonist against the Apelin receptor (Aplnr/Apj) attenuated Cdc42 activity and restored endothelial cell morphology and arteriovenous connection diameter in Rbpj-mutant brain vessels. CONCLUSIONS: Our data suggest that endothelial Rbpj promotes rearrangement of brain ECs during cerebrovascular remodeling, through Apelin/Apj-mediated small GTPase activity, and prevents bAVM. By inhibiting Apelin/Apj signaling in vivo, we demonstrated pharmacological prevention of Rbpj-mediated bAVM.

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Section: Discussionmentioning

confidence: 74%

Rbpj Deficiency Disrupts Vascular Remodeling via Abnormal Apelin and Cdc42 (Cell Division Cycle 42) Activity in Brain Arteriovenous Malformation

Adhicary

Fanelli

Nakisli

et al. 2023

Stroke

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“…The MAPK pathway is a classical inflammation-related pathway [ 39 ]. Western blot results confirmed that the phosphorylation levels of the Extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 proteins involved in the MAPK pathway were significantly increased after LPS stimulation of RAW264.7 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ginseng-derived nanoparticles alleviate inflammatory bowel disease via the TLR4/MAPK and p62/Nrf2/Keap1 pathways

Yang,

Li,

Bai

et al. 2024

J Nanobiotechnol

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Inflammatory bowel disease (IBD) is closely linked to the homeostasis of the intestinal environment, and exosomes can be used to treat IBD due to their high biocompatibility and ability to be effectively absorbed by the intestinal tract. However, Ginseng-derived nanoparticles (GDNPs) have not been studied in this context and their mechanism of action remains unclear. Here, we investigated GDNPs ability to mediate intercellular communication in a complex inflammatory microenvironment in order to treat IBD. We found that GDNPs scavenge reactive oxygen species from immune cells and intestinal epithelial cells, inhibit the expression of pro-inflammatory factors, promote the proliferation and differentiation of intestinal stem cells, as well as enhancing the diversity of the intestinal flora. GDNPs significantly stabilise the intestinal barrier thereby promoting tissue repair. Overall, we proved that GDNPs can ameliorate inflammation and oxidative stress in vivo and in vitro, acting on the TLR4/MAPK and p62/Keap1/Nrf2 pathways, and exerting an anti-inflammatory and antioxidant effect. GDNPs mitigated IBD in mice by reducing inflammatory factors and improving the intestinal environment. This study offers new evidence of the potential therapeutic effects of GDNPs in the context of IBD, providing the conceptual ground for an alternative therapeutic strategy. Graphical Abstract

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“…34,40 Recent research has suggested that APJ is co-localized with GLUT-1 on the membrane of HemECs and is highly expressed in proliferative IHs, with its negative regulation found to inhibit HemECs function via the MAPK/ERK pathway. 41 Nevertheless, the clinical applicability of APJ as a biomarker faces challenges due to its nature as a G-protein coupled receptor and its predominant membrane-bound distribution in IH tissues, restricting its presence in the bloodstream. Conversely, apelin can be secreted into circulation, 35 and thus may be a more appropriate indicator for IHs.…”

Section: Discussionmentioning

confidence: 99%

“…In neoplastic diseases, their overexpression is linked to enhanced angiogenesis and maturation of tumor vessels, 34,38,39 leading to their consideration as potential diagnostic and therapeutic biomarkers in various cancers 34,40 . Recent research has suggested that APJ is co‐localized with GLUT‐1 on the membrane of HemECs and is highly expressed in proliferative IHs, with its negative regulation found to inhibit HemECs function via the MAPK/ERK pathway 41 . Nevertheless, the clinical applicability of APJ as a biomarker faces challenges due to its nature as a G‐protein coupled receptor and its predominant membrane‐bound distribution in IH tissues, restricting its presence in the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

Serum apelin as a potential biomarker for infantile hemangiomas

Chen,

Zhang,

et al. 2024

Pediatric Blood & Cancer

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BackgroundInfantile hemangiomas (IHs) are common benign vascular tumors in infants. Apelin, an endogenous cytokine, is implicated in the angiogenesis of neoplastic diseases. We aimed to explore the association between apelin and IHs, providing a foundation for clinical applications.MethodsWe identified differential expression of apelin in proliferative IHs compared to healthy controls (HCs) through bioinformatics analysis of publicly available databases and verified by Immunofluorescence. Enzyme‐linked immunosorbent assay was used to quantify the serum levels of apelin and vascular endothelial growth factor (VEGF) in a cohort of 116 cases of proliferative IHs, 65 cases of capillary malformations (CMs), and 70 HCs.ResultsApelin and APJ (APLNR, apelin receptor) were identified as the significantly upregulated differentially expressed genes (DEGs) in proliferative IHs. Immunofluorescence staining indicated high expression of apelin in proliferative IHs, while minimal expression in non‐IH lesions. Apelin in IHs was reduced following 6 months of propranolol treatment. Serum apelin levels were significantly higher in the IH group compared to both the CM and HC groups. Moreover, apelin exhibited excellent discriminatory ability in distinguishing IHs from HCs, with an area under the curve (AUC) exceeding 0.90. A positive correlation was observed between the levels of apelin and the size of superficial IHs. The expression profiles of VEGF and apelin in IHs were found to be consistent.ConclusionsApelin shows promise as a potential biomarker for IHs. The association between apelin and IH size, as well as its responsiveness to propranolol treatment, indicates its possible utility as a valuable indicator for the therapeutic evaluation of IHs.

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Apelin Receptor Can Act as a Specific Marker and Promising Therapeutic Target for Infantile Hemangioma

Cited by 5 publications

References 54 publications

Rbpj Deficiency Disrupts Vascular Remodeling via Abnormal Apelin and Cdc42 (Cell Division Cycle 42) Activity in Brain Arteriovenous Malformation

Rbpj Deficiency Disrupts Vascular Remodeling via Abnormal Apelin and Cdc42 (Cell Division Cycle 42) Activity in Brain Arteriovenous Malformation

Ginseng-derived nanoparticles alleviate inflammatory bowel disease via the TLR4/MAPK and p62/Nrf2/Keap1 pathways

Serum apelin as a potential biomarker for infantile hemangiomas

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