The apelinergic system in the developing lung: Expression and signaling

Piairo, Paulina; Moura, Rute S.; Nogueira‐Silva, Cristina; Correia‐Pinto, Jorge

doi:10.1016/j.peptides.2011.10.010

Cited by 22 publications

(19 citation statements)

References 49 publications

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“…Many factors that regulate fetal lung branching morphogenesis activate signaling pathways that culminate with MAPK, PI3K/Akt and p38 cascades [30,31,40,41,42]. In the present study, ephrin-B1 was found not to modify the phosphorylated levels of these proteins.…”

Section: Discussioncontrasting

confidence: 53%

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

Peixoto

Pereira-Terra

Moura

et al. 2015

Cell Physiol Biochem

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Background/ Aims: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis. Methods: Ephrins-B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed. Results: Ephrin-B1 presents mesenchymal expression, whereas ephrin-B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development. Conclusion: Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters.

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Section: Discussioncontrasting

confidence: 53%

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

Peixoto

Pereira-Terra

Moura

et al. 2015

Cell Physiol Biochem

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“…In addition, co-transfection of the AR and B1R in HUVECs results in increased eNOS activation in response to either apelin or the B1R ligand des-Arg 9 -BK, suggesting that this AR-B1R heteromer may be involved in the vasodilatory effects of apelin (Bai et al 2014). Beyond these studies showing heteromer formation, Piairo et al (2011) observed AR dimers and higher order oligomers in the developing lung using western blotting, but these multimers were not conclusively identified as being either homomeric or heteromeric in nature.…”

Section: Ar Dimerization/oligomerization and Its Impact On Cell Signamentioning

confidence: 87%

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

Chapman

Dupré

Rainey

2014

Biochem. Cell Biol.

171

135

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The apelin receptor (AR or APJ) is a class A (rhodopsin-like) G-protein coupled receptor (GPCR) with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, apelin, induces diverse physiological effects including vasoconstriction and dilation; strengthening of heart muscle contractility; angiogenesis; and, regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ ELABELA, was identified as having a crucial role in zebrafish embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about mechanisms of peptide-AR activation. Additional complexity arises from modulation of the AR by two endogenous peptide ligands, both with multiple bioactive isoforms of variable length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other GPCRs. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR.

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“…Then, the lungs were transferred to porous membranes (Isopore™ membrane filters, Merck Millipore, Germany) and cultured for 4 days as previously described [28,30]. The culture medium was replaced every 48 hours.…”

Section: Fetal Lung Explant Culturementioning

confidence: 99%

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

Piairo

Moura

Baptista

et al. 2017

Cell Physiol Biochem

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Key Words Signal transducer and activator of transcription (STAT) • Suppressor of cytokine signaling (SOCS) • Congenital diaphragmatic hernia (CDH) • Lung development • NitrofenAbstract Background: Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. Methods: We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. Results: Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. Conclusion: These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH.

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The apelinergic system in the developing lung: Expression and signaling

Cited by 22 publications

References 49 publications

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

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