Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models

Karpinich, Natalie O.; Hoopes, Samantha L.; Kechele, Daniel O.; Lenhart, Patricia M.; Caron, Kathleen M.

doi:10.2174/157340211799304761

Cited by 40 publications

(46 citation statements)

References 185 publications

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“…Overexpression of FAK may result in the dysregulation of ADM expression. It was reported that ADM is a mediator in the crosstalk between mast and tumor cells, a stimulator of angiogenesis and mitosis of tumor cells and an apoptosis inhibitor of vascular endothelial cells (19,20). Therefore, ADM may have a critical function in tumor development and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer

Hong

Liao

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the expression of focal adhesion kinase (FAK) and adrenomedullin (ADM) and determine their clinical significance and cooperative role in human epithelial ovarian cancer. The expression of FAK and ADM was investigated in epithelial ovarian cancer, benign ovarian tumors and normal control tissues by immunohistochemical staining and optical microscopy. The FAK and ADM expression and correlation with clinicopathological parameters was analyzed using SPSS 13.0 software.

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Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer

Hong

Liao

et al. 2015

Oncology Letters

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“…Notably, on the basis of wide expression of CTL2, we found that the other cells may be involved in antibody-mediated effects in vivo. Inhibition of this pathway by substances that strengthen endothelial integrity, such as adrenomedullin, 55 would be an interesting, new approach in treating severe antibody-mediated TRALI.…”

Section: Discussionmentioning

confidence: 99%

Anti–Human Neutrophil Antigen-3a Induced Transfusion-Related Acute Lung Injury in Mice by Direct Disturbance of Lung Endothelial Cells

Bayat

Tjahjono

Sydykov

et al. 2013

ATVB

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Objective— Antibodies against human neutrophil antigen-3a (HNA-3a) located on choline transporter-like protein 2 induce severe transfusion-related acute lung injury (TRALI). This study aims to identify the mechanism implicated in anti–HNA-3a-mediated TRALI. Approach and Results— Our analysis shows that anti–HNA-3a recognizes 2 choline transporter-like protein 2 isoforms (P1 and P2) on human microvascular endothelial cells from lung blood vessels but reacts only with the P1 isoform on neutrophils. Direct treatment of HNA-3a–positive endothelial cells with anti–HNA-3a, but not with anti–HNA-3b, leads to reactive oxygen species production, increased albumin influx, and decreased endothelial resistance associated with the formation of actin stress filaments and loosening of junctional vascular endothelium-cadherin. In a novel in vivo mouse model, TRALI was documented by significant increase in lung water content, albumin concentration, and neutrophil numbers in the bronchoalveolar lavage on injection of human anti–HNA-3a in lipopolysaccharides-treated, as well as nontreated mice. Interestingly, although neutrophil depletion alleviated severity of lung injury, it failed to prevent TRALI in this model. Infusion of anti–HNA-3a F(ab′) 2 fragments caused moderate TRALI. Finally, mice lacking nicotinamide adenine dinucleotide phosphate oxidase (NOX2 y/ - ) were protected from anti–HNA-3a-mediated TRALI. Conclusions— These data demonstrate the initiation of endothelial barrier dysfunction in vitro and in vivo by direct binding of anti–HNA-3a on endothelial cells. It seems, however, that the presence of neutrophils aggravates barrier dysfunction. This novel mechanism of TRALI primarily mediated by endothelial cell dysfunction via choline transporter-like protein 2 may help to define new treatment strategies to decrease TRALI-related mortality.

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“…3,4 AM also has cardioprotective functions and plays a role in normal pregnancy and pregnancy complications. 4,5 In addition, CGRP and AM both exhibit angiogenic activity. 6,7 As a consequence of the various actions of CGRP and AM and their involvement in several pathophysiological states, their receptors are of interest as drug targets for a variety of disorders including migraine headache, acute myocardial infarction, pulmonary hypertension, preeclampsia, sepsis, and cancer.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 As a consequence of the various actions of CGRP and AM and their involvement in several pathophysiological states, their receptors are of interest as drug targets for a variety of disorders including migraine headache, acute myocardial infarction, pulmonary hypertension, preeclampsia, sepsis, and cancer. 4,[8][9][10] The CGRP and AM receptors are heteromeric protein complexes comprised of the calcitonin receptor-like receptor (CLR), a class B/Secretin family G protein-coupled receptor (GPCR), in association with a receptor activity modifying protein (RAMP).…”

Section: Introductionmentioning

confidence: 99%

Selective CGRP and adrenomedullin peptide binding by tethered RAMP‐calcitonin receptor‐like receptor extracellular domain fusion proteins

Moad

Pioszak

2013

Protein Science

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Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are related peptides that are potent vasodilators. The CGRP and AM receptors are heteromeric protein complexes comprised of a shared calcitonin receptor-like receptor (CLR) subunit and a variable receptor activity modifying protein (RAMP) subunit. RAMP1 enables CGRP binding whereas RAMP2 confers AM specificity. How RAMPs determine peptide selectivity is unclear and the receptor stoichiometries are a topic of debate with evidence for 1:1, 2:2, and 2:1 CLR:RAMP stoichiometries. Here, we describe bacterial production of recombinant tethered RAMP-CLR extracellular domain (ECD) fusion proteins and biochemical characterization of their peptide binding properties. Tethering the two ECDs ensures complex stability and enforces defined stoichiometry. The RAMP1-CLR ECD fusion purified as a monomer, whereas the RAMP2-CLR ECD fusion purified as a dimer. Both proteins selectively bound their respective peptides with affinities in the low micromolar range. Truncated CGRP(27-37) and AM(37-52) fragments were identified as the minimal ECD complex binding regions. The CGRP C-terminal amide group contributed to, but was not required for, ECD binding, whereas the AM C-terminal amide group was essential for ECD binding. Alanine-scan experiments identified CGRP residues T30, V32, and F37 and AM residues P43, K46, I47, and Y52 as critical for ECD binding. Our results identify CGRP and AM determinants for receptor ECD complex binding and suggest that the CGRP receptor functions as a 1:1 heterodimer. In contrast, the AM receptor may function as a 2:2 dimer of heterodimers, although our results cannot rule out 2:1 or 1:1 stoichiometries.

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Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models

Cited by 40 publications

References 185 publications

Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer

Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer

Anti–Human Neutrophil Antigen-3a Induced Transfusion-Related Acute Lung Injury in Mice by Direct Disturbance of Lung Endothelial Cells

Selective CGRP and adrenomedullin peptide binding by tethered RAMP‐calcitonin receptor‐like receptor extracellular domain fusion proteins

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