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 and José López-Barneo ()
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Alejandro Moreno-Domínguez: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Olalla Colinas: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Ignacio Arias-Mayenco: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
José M. Cabeza: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Juan L. López-Ogayar: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Navdeep S. Chandel: Northwestern University
Norbert Weissmann: Justus-Liebig-University
Natascha Sommer: Justus-Liebig-University
Alberto Pascual: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
José López-Barneo: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51023-3

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