Constitutive Store-Operated Ca2+ Entry Leads to Enhanced Nitric Oxide Production and Proliferation in Infantile Hemangioma-Derived Endothelial Colony-Forming Cells

Estella Zuccolo, Cinzia Bottino, Federica Diofano, Valentina Poletto, Alessia Claudia Codazzi, Savina Mannarino, Rita Campanelli, Gabriella Fois, Gian Luigi Marseglia, Germano Guerra, Daniela Montagna, Umberto Laforenza, Vittorio Rosti, Margherita Massa, Francesco Moccia

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Abstract

Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca2+ toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca2+ entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca2+ signalosome is altered in IH-ECFCs by employing Ca2+ and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca2+ release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La3+, and Pyr6 and recharges the intracellular Ca2+ pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH.

Original languageEnglish
Pages (from-to)301-319
Number of pages19
JournalStem Cells and Development
Volume25
Issue number4
DOIs
Publication statusPublished - Feb 15 2016

Fingerprint

Hemangioma
Nitric Oxide
Blood Vessels
Pharmacology
Growth
Vascular Endothelial Growth Factor A
Real-Time Polymerase Chain Reaction
Neoplasms
Up-Regulation
Endothelial Cells
Adenosine Triphosphate
Western Blotting
Cell Proliferation
Hemorrhage
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

@article{7e55cdca887845968270317e7592b99a,
title = "Constitutive Store-Operated Ca2+ Entry Leads to Enhanced Nitric Oxide Production and Proliferation in Infantile Hemangioma-Derived Endothelial Colony-Forming Cells",
abstract = "Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca2+ toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca2+ entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca2+ signalosome is altered in IH-ECFCs by employing Ca2+ and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca2+ release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La3+, and Pyr6 and recharges the intracellular Ca2+ pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH.",
author = "Estella Zuccolo and Cinzia Bottino and Federica Diofano and Valentina Poletto and Codazzi, {Alessia Claudia} and Savina Mannarino and Rita Campanelli and Gabriella Fois and Marseglia, {Gian Luigi} and Germano Guerra and Daniela Montagna and Umberto Laforenza and Vittorio Rosti and Margherita Massa and Francesco Moccia",
year = "2016",
month = "2",
day = "15",
doi = "10.1089/scd.2015.0240",
language = "English",
volume = "25",
pages = "301--319",
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issn = "1547-3287",
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T1 - Constitutive Store-Operated Ca2+ Entry Leads to Enhanced Nitric Oxide Production and Proliferation in Infantile Hemangioma-Derived Endothelial Colony-Forming Cells

AU - Zuccolo, Estella

AU - Bottino, Cinzia

AU - Diofano, Federica

AU - Poletto, Valentina

AU - Codazzi, Alessia Claudia

AU - Mannarino, Savina

AU - Campanelli, Rita

AU - Fois, Gabriella

AU - Marseglia, Gian Luigi

AU - Guerra, Germano

AU - Montagna, Daniela

AU - Laforenza, Umberto

AU - Rosti, Vittorio

AU - Massa, Margherita

AU - Moccia, Francesco

PY - 2016/2/15

Y1 - 2016/2/15

N2 - Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca2+ toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca2+ entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca2+ signalosome is altered in IH-ECFCs by employing Ca2+ and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca2+ release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La3+, and Pyr6 and recharges the intracellular Ca2+ pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH.

AB - Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca2+ toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca2+ entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca2+ signalosome is altered in IH-ECFCs by employing Ca2+ and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca2+ release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La3+, and Pyr6 and recharges the intracellular Ca2+ pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH.

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