Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation

María Rodríguez-Moyano, Ignacio Díaz, Natalia Dionisio, Xuexin Zhang, Javier Ávila-Medina, Eva Calderón-Sánchez, Mohamed Trebak, Juan Antonio Rosado, Antonio Ordóñez, Tarik Smani

Research output: Contribution to journalArticle

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Abstract

Aims: Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca2+)-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca2+ entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. Methods and results: We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca2+ mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca2+ concentration ([Ca2+]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd3+-sensitive current with similar features of the Ca2+ release-activated Ca2+ current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca2+/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca2+/calmodulin- dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca2+ influx, CREB activation and VSMCs proliferation. Conclusion: Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

Original languageEnglish (US)
Pages (from-to)297-306
Number of pages10
JournalCardiovascular Research
Volume100
Issue number2
DOIs
StatePublished - Nov 1 2013

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Growth Factor Receptors
Vascular Smooth Muscle
Transcriptional Activation
Smooth Muscle Myocytes
Epithelium
Cell Proliferation
Calcium
Cyclic AMP Response Element-Binding Protein
Calcium-Calmodulin-Dependent Protein Kinases
Extracellular Signal-Regulated MAP Kinases
urotensin II
Bromodeoxyuridine
Immunoprecipitation
Aorta
Wistar Rats
Atherosclerosis
Peptides
Stromal Interaction Molecule 1

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Rodríguez-Moyano, M., Díaz, I., Dionisio, N., Zhang, X., Ávila-Medina, J., Calderón-Sánchez, E., ... Smani, T. (2013). Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation. Cardiovascular Research, 100(2), 297-306. https://doi.org/10.1093/cvr/cvt196
Rodríguez-Moyano, María ; Díaz, Ignacio ; Dionisio, Natalia ; Zhang, Xuexin ; Ávila-Medina, Javier ; Calderón-Sánchez, Eva ; Trebak, Mohamed ; Rosado, Juan Antonio ; Ordóñez, Antonio ; Smani, Tarik. / Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation. In: Cardiovascular Research. 2013 ; Vol. 100, No. 2. pp. 297-306.
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abstract = "Aims: Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca2+)-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca2+ entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. Methods and results: We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca2+ mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca2+ concentration ([Ca2+]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd3+-sensitive current with similar features of the Ca2+ release-activated Ca2+ current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca2+/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca2+/calmodulin- dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca2+ influx, CREB activation and VSMCs proliferation. Conclusion: Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.",
author = "Mar{\'i}a Rodr{\'i}guez-Moyano and Ignacio D{\'i}az and Natalia Dionisio and Xuexin Zhang and Javier {\'A}vila-Medina and Eva Calder{\'o}n-S{\'a}nchez and Mohamed Trebak and Rosado, {Juan Antonio} and Antonio Ord{\'o}{\~n}ez and Tarik Smani",
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Rodríguez-Moyano, M, Díaz, I, Dionisio, N, Zhang, X, Ávila-Medina, J, Calderón-Sánchez, E, Trebak, M, Rosado, JA, Ordóñez, A & Smani, T 2013, 'Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation', Cardiovascular Research, vol. 100, no. 2, pp. 297-306. https://doi.org/10.1093/cvr/cvt196

Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation. / Rodríguez-Moyano, María; Díaz, Ignacio; Dionisio, Natalia; Zhang, Xuexin; Ávila-Medina, Javier; Calderón-Sánchez, Eva; Trebak, Mohamed; Rosado, Juan Antonio; Ordóñez, Antonio; Smani, Tarik.

In: Cardiovascular Research, Vol. 100, No. 2, 01.11.2013, p. 297-306.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation

AU - Rodríguez-Moyano, María

AU - Díaz, Ignacio

AU - Dionisio, Natalia

AU - Zhang, Xuexin

AU - Ávila-Medina, Javier

AU - Calderón-Sánchez, Eva

AU - Trebak, Mohamed

AU - Rosado, Juan Antonio

AU - Ordóñez, Antonio

AU - Smani, Tarik

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Aims: Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca2+)-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca2+ entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. Methods and results: We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca2+ mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca2+ concentration ([Ca2+]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd3+-sensitive current with similar features of the Ca2+ release-activated Ca2+ current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca2+/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca2+/calmodulin- dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca2+ influx, CREB activation and VSMCs proliferation. Conclusion: Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

AB - Aims: Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca2+)-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca2+ entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. Methods and results: We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca2+ mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca2+ concentration ([Ca2+]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd3+-sensitive current with similar features of the Ca2+ release-activated Ca2+ current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca2+/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca2+/calmodulin- dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca2+ influx, CREB activation and VSMCs proliferation. Conclusion: Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

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