Calcitonin Gene-Related Peptide (CALCA) Is a Proangiogenic Growth Factor in the Human Placental Development1

Dong, Yi; Reddy, Deepti M.; Green, Kortney E.; Chauhan, Madhu; Wang, Hui Qun; Nagamani, Manubai; Hankins, Gary D.V.; Yallampalli, Chandra

doi:10.1095/biolreprod.106.059089

Cited by 36 publications

(34 citation statements)

References 30 publications

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“…Moreover, the results of the experiments in which only CLR/RAMP1 or CLR/RAMP2 were antagonized (by using the specific inhibitors CGRP or AM , respectively) suggest that the two receptors mediated the morphogenetic response in HUVECs, being that the effect of IMD only partially inhibited in this experimental condition. This finding is not surprising, being consistent with previously reported data demostrating that both CGRP (11,12,31), specific ligand of CLR/RAMP1, and AM (14,15), specific ligand of CLR/RAMP2, have a clearcut pro-angiogenic effect on human vascular ECs.…”

Section: Discussionsupporting

confidence: 93%

Involvement of vascular endothelial growth factor signaling in CLR/RAMP1 and CLR/RAMP2-mediated pro-angiogenic effect of intermedin on human vascular endothelial cells

Albertin

Sorato²,

Oselladore³

et al. 2010

Int J Mol Med

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Abstract. Intermedin (IMD) is a recently discovered peptide closely related to adrenomedullin. Its principal physiological activity is its role in the regulation of the cardiovascular system, where it exerts a potent hypotensive effect. In addition, data were recently provided showing that this peptide is able to exert a clearcut pro-angiogenic effect both in vitro and in vivo. IMD acts through the non-selective interaction with receptor complexes formed by the dimerization of calcitoninlike receptor (CLR) with the receptor activity-modifying proteins RAMP1, 2 or 3. Thus, in the present study, the role of CLR/RAMP complexes in mediating the pro-angiogenic effect induced by IMD on human umbilical vein endothelial cells (HUVECs) cultured on Matrigel was examined. Real-time PCR demonstrated the expression of IMD, CLR/RAMP1 and CLR/RAMP2 (but not CLR/RAMP3) mRNA in HUVECs. IMD exerted a significant in vitro angiogenic action, specifically triggered by the binding of the peptide to CLR/RAMP complexes. Both CLR/RAMP1 and CLR/RAMP2 appeared to mediate the pro-angiogenic effect, which was associated with a significant increase of vascular endothelial growth factor (VEGF) mRNA expression 18 h following IMD administration, indicating that the observed pro-angiogenic effects are related, at least in part, to an increased synthesis of this growth factor promoted by the peptide. Western blot analysis, however, showed a significant increase of VEGF receptor-2 phosphorylation as early as 5 min following IMD administration, indicating that IMD induces a pro-angiogenic response in human vascular endothelial cells not only via CLR/RAMP-induced release of VEGF, but also during signal initiation and propagation by transactivating the VEGF receptor-2 machinery.

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Section: Discussionsupporting

confidence: 93%

Involvement of vascular endothelial growth factor signaling in CLR/RAMP1 and CLR/RAMP2-mediated pro-angiogenic effect of intermedin on human vascular endothelial cells

Albertin

Sorato²,

Oselladore³

et al. 2010

Int J Mol Med

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“…Failure of successful invasion leads to clinicopathological conditions such as intrauterine growth retardation, preeclampsia, and others [18]. CALCB and ADM have been reported to function as angiogenic agents in placental development [6,19]. The ADM-null mutation (ADM À/À ) is embryonically lethal, and no embryos survive beyond the midterm of gestation, indicating an indispensable role of ADM in early placental development and fetal morphogenesis [20].…”

Section: Discussionmentioning

confidence: 99%

“…CALCB and ADM are expressed by the placenta, along with the complete receptor system for these peptides [19,24]. ADM2 has the highest structural homology with the ADM peptide [1].…”

Section: Discussionmentioning

confidence: 99%

Expression of Adrenomedullin 2 (ADM2)/Intermedin (IMD) in Human Placenta: Role in Trophoblast Invasion and Migration1

Chauhan

Yallampalli

Dong

et al. 2009

Biology of Reproduction

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Calcitonin gene-related peptide (CALCB), amylin, and adrenomedullin (ADM) belong to a unique group of calcitonin (CALCA)/CALCB family peptides that have overlapping biological effects owing to their structure and cross-reactivity between receptors. CALCB and ADM are expressed in fetoplacental tissues and are important in maintaining normal placental function. Recently, ADM 2 (ADM2)/intermedin was identified as a novel CALCA/CALCB family peptide that functions through CALCB and ADM receptors. ADM2 is expressed in the pituitary, digestive tract, and other organs of vertebrates and reduces blood pressure in both normal and hypertensive rats. We recently reported that the level of immunoreactive ADM2 is significantly upregulated in pregnant rats and that its hypotensive effects are also increased during rat pregnancy. Furthermore, infusion of ADM2 antagonist in pregnant rats causes fetoplacental growth restriction. The objective of this study was to analyze the expression and possible role of ADM2 in human placenta. We show that ADM2 mRNA is expressed in human placenta and that immunoreactive ADM2 is localized in syncytiotrophoblasts, cytotrophoblasts, and endothelial cells throughout human pregnancy. This study also demonstrates that ADM2 enhances the invasion and migration of first-trimester HTR-8SV/neo cells. ADM2 increases the invasive index of HTR-8SV/neo cells by 2.2-fold compared with controls. Taken together, the findings from this study suggest that ADM2 may have a role in the physiology of human pregnancy via regulation of trophoblast invasion and migration.

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“…Also discovered through a proteomics approach in CRC was proteasome (prosome, macropain) activator subunit 3, a proteasome-associated protein that was recently identified as a novel serum tumor marker in this cancer type (65). The expression of calcitonin-related polypeptide alpha, a peptide associated with increased angiogenesis and endothelial cell proliferation in placental development, but not previously associated with cancer, was higher in ADC versus normal tissue (66). Notably, the mini-chromosome maintenance (MCM) proteins, MCM2, MCM3, MCM4, MCM5, and MCM6, were also present in our list of up-regulated proteins.…”

Section: Gene Ontology Enrichment Analysis Of Adc Versus Scc Reveals mentioning

confidence: 99%

In-depth Proteomic Analysis of Nonsmall Cell Lung Cancer to Discover Molecular Targets and Candidate Biomarkers

Kikuchi

Hassanein

Amann

et al. 2012

Molecular & Cellular Proteomics

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Advances in proteomic analysis of human samples are driving critical aspects of biomarker discovery and the identification of molecular pathways involved in disease etiology. Toward that end, in this report we are the first to use a standardized shotgun proteomic analysis method for in-depth tissue protein profiling of the two major subtypes of nonsmall cell lung cancer and normal lung tissues. We identified 3621 proteins from the analysis of pooled human samples of squamous cell carcinoma, adenocarcinoma, and control specimens. In addition to proteins previously shown to be implicated in lung cancer, we have identified new pathways and multiple new differentially expressed proteins of potential interest as therapeutic targets or diagnostic biomarkers, including some that were not identified by transcriptome profiling. Up-regulation of these proteins was confirmed by multiple reaction monitoring mass spectrometry. A subset of these proteins was found to be detectable and differentially present in the peripheral blood of cases and matched controls. Label-free shotgun proteomic analysis allows definition of lung tumor proteomes, identification of biomarker candidates, and potential targets for therapy. Molecular & Cellular Proteomics 11: 10.1074/mcp.M111.015370, 916 -932, 2012.Lung cancer is one of the deadliest cancers, with ϳ200,000 newly diagnosed individuals and 160,000 deaths every year in the United States (1). Despite the most advanced treatments that modern medicine has to offer, the five-year survival rate remains less than 15%. Although a small subset of tumors have been found to be driven by single mutated oncogenes for which active, but still noncurative, therapies are available, the vast majority of patients have complex multifactorial disease with few effective therapeutic options. New early detection strategies and molecular therapeutic targets are urgently needed to improve patient survival.Genomic analysis has enabled us to measure the sequence, copy number, and expression changes of thousands of genes simultaneously, which can be used to discover transcripts specifically altered or expressed in tumor tissues (2-4). Although genomic studies have given important new insights into the mechanisms of carcinogenesis, therapeutic targets, and most practical biomarkers are their protein products, and the correlation between transcript sequence or level and protein function remains complex and poorly understood. Protein expression, in part, depends on transcript levels, but it is clear that significant translational and post-translational regulation of protein levels and function occurs, adding another level of complexity in the regulation of activity, especially in tumor cells (5, 6). It would be ideal to have a comprehensive understanding of the novel changes in protein expression levels and the modifications of proteins in cancer cells, but the technology to directly study proteomes has lagged behind that to assess genomes and transcriptomes. We and others have used matrix-assisted laser desorption and...

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Calcitonin Gene-Related Peptide (CALCA) Is a Proangiogenic Growth Factor in the Human Placental Development1

Cited by 36 publications

References 30 publications

Involvement of vascular endothelial growth factor signaling in CLR/RAMP1 and CLR/RAMP2-mediated pro-angiogenic effect of intermedin on human vascular endothelial cells

Involvement of vascular endothelial growth factor signaling in CLR/RAMP1 and CLR/RAMP2-mediated pro-angiogenic effect of intermedin on human vascular endothelial cells

Expression of Adrenomedullin 2 (ADM2)/Intermedin (IMD) in Human Placenta: Role in Trophoblast Invasion and Migration1

In-depth Proteomic Analysis of Nonsmall Cell Lung Cancer to Discover Molecular Targets and Candidate Biomarkers

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