Hif1α-dependent mitochondrial acute O2 sensing and signaling to myocyte Ca2+ channels mediate arterial hypoxic vasodilation

Alejandro Moreno-Domínguez; Olalla Colinas; Ignacio Arias-Mayenco; José M. Cabeza; Juan L. López-Ogayar; Navdeep S. Chandel; Norbert Weissmann; Natascha Sommer; Alberto Pascual; José López-Barneo

doi:10.1038/s41467-024-51023-3

Hif1α-dependent mitochondrial acute O₂ sensing and signaling to myocyte Ca²⁺ channels mediate arterial hypoxic vasodilation

Alejandro Moreno-Domínguez, Olalla Colinas, Ignacio Arias-Mayenco, José M. Cabeza, Juan L. López-Ogayar, Navdeep S. Chandel, Norbert Weissmann, Natascha Sommer, Alberto Pascual, José López-Barneo^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Vasodilation in response to low oxygen (O₂) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O₂ supply to tissues according to demand. However, how blood vessels react to O₂ deficiency is not well understood. A common belief is that arterial myocytes are O₂-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca²⁺channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O₂ modulation of Ca²⁺ channels and hypoxic vasodilation. Mitochondria function as O₂ sensors and effectors that signal myocyte Ca²⁺ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O₂-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology.

Original language	English (US)
Article number	6649
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-51023-3
State	Published - Dec 2024

Funding

This research was supported by the Spanish Ministries of Science and Innovation and Health (Grants SAF2016-74990-R, JL-B. and PID2019-106410RB-I00, J.L.-B. funded by MCIN/AEI/10.13039/501100011033, and the European Research Council (ERC Advanced Grant PRJ201502629, J.L.-B.). We thank Dr. Juan Luis Ribas (CITIUS, University of Seville) for help with electron microscopy. We also thank the staff of IBiS and \u201CCentro de Producci\u00F3n y Experimentaci\u00F3n Animal Oscar Pintado\u201D for technical assistance.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-024-51023-3

Cite this

Moreno-Domínguez, A., Colinas, O., Arias-Mayenco, I., Cabeza, J. M., López-Ogayar, J. L., Chandel, N. S., Weissmann, N., Sommer, N., Pascual, A., & López-Barneo, J. (2024). Hif1α-dependent mitochondrial acute O₂ sensing and signaling to myocyte Ca²⁺ channels mediate arterial hypoxic vasodilation. Nature communications, 15(1), Article 6649. https://doi.org/10.1038/s41467-024-51023-3

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abstract = "Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology.",

author = "Alejandro Moreno-Dom{\'i}nguez and Olalla Colinas and Ignacio Arias-Mayenco and Cabeza, {Jos{\'e} M.} and L{\'o}pez-Ogayar, {Juan L.} and Chandel, {Navdeep S.} and Norbert Weissmann and Natascha Sommer and Alberto Pascual and Jos{\'e} L{\'o}pez-Barneo",

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Moreno-Domínguez, A, Colinas, O, Arias-Mayenco, I, Cabeza, JM, López-Ogayar, JL, Chandel, NS, Weissmann, N, Sommer, N, Pascual, A & López-Barneo, J 2024, 'Hif1α-dependent mitochondrial acute O₂ sensing and signaling to myocyte Ca²⁺ channels mediate arterial hypoxic vasodilation', Nature communications, vol. 15, no. 1, 6649. https://doi.org/10.1038/s41467-024-51023-3

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AU - Cabeza, José M.

AU - López-Ogayar, Juan L.

AU - Chandel, Navdeep S.

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