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Kv1.3 channels modulate human vascular smooth muscle cells proliferation independently of mTOR signaling pathway

  • Ion channels, receptors and transporters
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Phenotypic modulation (PM) of vascular smooth muscle cells (VSMCs) is central to the process of intimal hyperplasia which constitutes a common pathological lesion in occlusive vascular diseases. Changes in the functional expression of Kv1.5 and Kv1.3 currents upon PM in mice VSMCs have been found to contribute to cell migration and proliferation. Using human VSMCs from vessels in which unwanted remodeling is a relevant clinical complication, we explored the contribution of the Kv1.5 to Kv1.3 switch to PM. Changes in the expression and the functional contribution of Kv1.3 and Kv1.5 channels were studied in contractile and proliferating VSMCs obtained from human donors. Both a Kv1.5 to Kv1.3 switch upon PM and an anti-proliferative effect of Kv1.3 blockers on PDGF-induced proliferation were observed in all vascular beds studied. When investigating the signaling pathways modulated by the blockade of Kv1.3 channels, we found that anti-proliferative effects of Kv1.3 blockers on human coronary artery VSMCs were occluded by selective inhibition of MEK/ERK and PLCγ signaling pathways, but were unaffected upon blockade of PI3K/mTOR pathway. The temporal course of the anti-proliferative effects of Kv1.3 blockers indicates that they have a role in the late signaling events essential for the mitogenic response to growth factors. These findings establish the involvement of Kv1.3 channels in the PM of human VSMCs. Moreover, as current therapies to prevent restenosis rely on mTOR blockers, our results provide the basis for the development of novel, more specific therapies.

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Acknowledgments

We thank Rodrigo de Pedro for the excellent technical assistance.

Funding

Supported by grants from the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (RIC RD12/0042/0006, Red Heracles), Ministerio de Ciencia e Innovación (BFU2010-15898 to MTPG), Junta de Castilla y León (VA094A11-2 to, JRLL), and Fondo de Investigaciones Sanitarias (FIS PI11/00225 to MR).

Ethical standard

For human samples, informed consent was given prior to inclusion. Protocols conforming the Declaration of Helsinki were approved by the Human Investigation Ethics Committees of the respective Hospitals.

All the experimental work performed complies with the Spanish legislation.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC, Edificio IBGM, c/ Sanz y Forés s/n, 47003, Valladolid, Spain

    Pilar Cidad, Eduardo Miguel-Velado, Christian Ruiz-McDavitt, Esperanza Alonso, Laura Jiménez-Pérez, Agustín Asuaje, Yamila Carmona, Daniel García-Arribas, M. Teresa Pérez-García & José Ramón López-López

  2. Servicio de Cardiología y Cirugía Cardíaca, Hospital Clínico Universitario, Valladolid, Spain

    Javier López & Mirella Fernández

  3. Servicio de Nefrología, Hospital Clínico Universitario, Valladolid, Spain

    Yngrid Marroquín

  4. Servicio de Cardiología. Institut Clinic del Tòrax, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, Spain

    Mercè Roqué

Authors
  1. Pilar Cidad
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  2. Eduardo Miguel-Velado
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  11. Mirella Fernández
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  13. M. Teresa Pérez-García
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  14. José Ramón López-López
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Correspondence to M. Teresa Pérez-García.

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Pilar Cidad and Eduardo Miguel-Velado equal contributors

M. Teresa Pérez-García and José Ramón López-López shared last authorship

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Cidad, P., Miguel-Velado, E., Ruiz-McDavitt, C. et al. Kv1.3 channels modulate human vascular smooth muscle cells proliferation independently of mTOR signaling pathway. Pflugers Arch - Eur J Physiol 467, 1711–1722 (2015). https://doi.org/10.1007/s00424-014-1607-y

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