Adrenomedullin Expression in the Developing Human Fetal Lung

Ramos, Carlos G.; Sun, Xi; Johnson, Eric B.; Nelson, Harold E.; Bosc, Laura V. González

doi:10.2310/jim.0000000000000020

Cited by 8 publications

(3 citation statements)

References 32 publications

(49 reference statements)

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“…Interestingly, the peak expression of AM and its signaling receptors occurred in the time period during which alveolarization occurs in mice. Ramos and colleagues demonstrated a similar finding in the developing human fetal lung [33]. In the lungs, AM and its receptors are co-expressed mainly in endothelial cells and epithelial cells of the airway and alveoli [34–36], suggesting that the effects of AM occur via autocrine and paracrine mechanisms.…”

Section: Resultsmentioning

confidence: 76%

Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

Menon

Shrestha

Shivanna

2017

Biochemical and Biophysical Research Communications

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Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of human infants that is characterized by disrupted lung angiogenesis. Adrenomedullin (AM) is a multifunctional peptide with angiogenic and vasoprotective properties. AM signals via its cognate receptors, calcitonin receptor-like receptor (Calcrl) and receptor activity-modifying protein 2 (RAMP2). Whether hyperoxia affects the pulmonary AM signaling pathway in neonatal mice and whether AM promotes lung angiogenesis in human infants are unknown. Therefore, we tested the following hypotheses: (1) hyperoxia exposure will disrupt AM signaling during the lung development period in neonatal mice; and (2) AM will promote angiogenesis in fetal human pulmonary artery endothelial cells (HPAECs) via extracellular signal-regulated kinases (ERK) 1/2 activation. We initially determined AM, Calcrl, and RAMP2 mRNA levels in mouse lungs on postnatal days (PND) 3, 7, 14, and 28. Next we determined the mRNA expression of these genes in neonatal mice exposed to hyperoxia (70% O2) for up to 14 d. Finally, using HPAECs, we evaluated if AM activates ERK1/2 and promotes tubule formation and cell migration. Lung AM, Calcrl, and RAMP2 mRNA expression increased from PND 3 and peaked at PND 14, a time period during which lung development occurs in mice. Interestingly, hyperoxia exposure blunted this peak expression in neonatal mice. In HPAECs, AM activated ERK1/2 and promoted tubule formation and cell migration. These findings support our hypotheses, emphasizing that AM signaling axis is a potential therapeutic target for human infants with BPD.

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Section: Resultsmentioning

confidence: 76%

Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

Menon

Shrestha

Shivanna

2017

Biochemical and Biophysical Research Communications

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“…Mutation in the ATP Binding Cassette Subfamily C Member 8 (ABCC8) gene is associated with pulmonary arterial hypertension (38). Receptor Activity-Modifying Protein 3 (RAMP3), the top hypomethylated gene with exposure to HCA, plays a role in human lung development (39). An additional top hypermethylated gene is Anterior Gradient 2 (AGR2), a protein disulfide isomerase family member known to be involved in asthma and allergen-induced mucin production (24).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Profile in Human Cord Blood Mononuclear Leukocytes From Term Neonates: Effects of Histological Chorioamnionitis

et al. 2020

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Background: Histological chorioamnionitis (HCA) is an infection/inflammation of fetal membranes and complicates 5.2-28.5% of all live births. Exposure to HCA can have long-term consequences including abnormal neurodevelopment and an increased risk for allergic disorders and asthma later in childhood. HCA may incite epigenetic changes, which have the potential to modulate both the immune and neurological systems as well as increase the risk of related disorders later in life. However, there is limited data on the impact of HCA on epigenetics, in particular DNA methylation, and changes to immune and neurological systems in full-term human neonates. Objective: To determine differential DNA methylation in cord blood mononuclear leukocytes from neonates exposed to HCA. Methods: Cord blood was collected from 10 term neonates (5 with HCA and 5 controls without HCA) and mononuclear leukocytes were isolated. Genome-wide DNA methylation screening was performed on Genomic DNA extracted from mononuclear leukocytes. Results: Mononuclear leukocytes from cord blood of HCA-exposed neonates showed differential DNA methylation of 68 probe sets compared to the control group (44 hypermethylated, 24 hypomethylated) with a p ≤ 0.0001. Several genes involved in immune modulation and nervous system development were found to be differentially methylated. Important canonical pathways as revealed by Ingenuity Pathway Analysis (IPA) were CREB Signaling in Neurons, FcγRIIB Signaling in B Lymphocytes, Cell Cycle:

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“…Recently, ADM and the AM 1 receptor have been found to be involved in the development of the fetal lung [125]. In adults, ADM exhibits potent pulmonary vasodilating and bronchodilating effects and is involved in the regulation of the pulmonary vascular tonus [126][127][128].…”

Section: Lungmentioning

confidence: 99%

Adrenomedullin – new perspectives of a potent peptide hormone

Schönauer

Els‐Heindl

Beck‐Sickinger

2017

Journal of Peptide Science

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Adrenomedullin (ADM) is a 52-amino acid multifunctional peptide, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones. ADM exhibits a significant vasodilatory potential and plays a key role in various regulatory mechanisms, predominantly in the cardiovascular and lymphatic system. It exerts its effects by activation of the calcitonin receptor-like receptor associated with one of the receptor activity-modifying proteins 2 or 3. ADM was first isolated from human phaeochromocytoma in 1993. Numerous studies revealed a widespread distribution in various tissues and organs, which is reflected by its multiple physiological roles in health and disease. Because of its anti-inflammatory, anti-apoptotic and proliferative properties, ADM exhibits potent protective functions under diverse pathological conditions, but it is also critically involved in tumor progression. ADM has therefore raised great interest in therapeutic applications and several clinical trials already revealed promising results. However, because the receptor activation mode has not yet been fully elucidated, a rational design of potent and selective ligands is still challenging. Detailed information on the binding mode of ADM from a recently reported crystal structure as well as efforts to improve its plasma stability and bioavailability may help to overcome these limitations in the future. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Adrenomedullin Expression in the Developing Human Fetal Lung

Cited by 8 publications

References 32 publications

Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

DNA Methylation Profile in Human Cord Blood Mononuclear Leukocytes From Term Neonates: Effects of Histological Chorioamnionitis

Adrenomedullin – new perspectives of a potent peptide hormone

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