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ORIGINAL RESEARCH article

Front. Physiol.
Sec. Vascular Physiology
Volume 15 - 2024 | doi: 10.3389/fphys.2024.1479882
This article is part of the Research Topic Physiological and Pathological Responses to Hypoxia and High Altitude, Volume III View all articles

Long term hypoxia modulates depolarization activation of BKCa currents in fetal sheep middle cerebral arterial myocytes

Provisionally accepted
Nikitha Nelapudi Nikitha Nelapudi 1Madison Boskind Madison Boskind 1Xiang-Qun Hu Xiang-Qun Hu 1David Mallari David Mallari 1Michelle Chan Michelle Chan 1Devin Wilson Devin Wilson 1Monica Romero Monica Romero 1Eris Albert-Minckler Eris Albert-Minckler 1Lubo Zhang Lubo Zhang 1Arlin B. Blood Arlin B. Blood 1Christopher G. Wilson Christopher G. Wilson 1Jose L. Puglisi Jose L. Puglisi 2SEAN M. WILSON SEAN M. WILSON 1*
  • 1 School of Medicine, Loma Linda University, Loma Linda, United States
  • 2 California Northstate University, Elk Grove, California, United States

The final, formatted version of the article will be published soon.

    Previous evidence indicates that gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of cytosolic Ca 2+ in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca 2+ signals can offer insight into the pathophysiological disruptions taking place in hypoxia-related perinatal cerebrovascular disease. This study aimed to determine the extent to which gestational hypoxia disrupts local Ca 2+ sparks and whole-cell Ca 2+ signals and coupling with BKCa channel activity. Confocal imaging of cytosolic Ca 2+ and recording BKCa currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (~140 days of gestation) from ewes held at low-(700 m) and high-altitude (3801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 μM ryanodine (Ry), to block RyR mediated Ca 2+ release. Membrane depolarization increased Ry-sensitive Ca 2+ spark frequency in normoxic and LTH groups along with BKCa activity. LTH reduced Ca 2+ spark and whole-cell Ca 2+ activity and induced a large leftward shift in the voltage-dependence of BKCa current activation. The influence of LTH on the spatial and temporal aspects of Ca 2+ sparks and whole-cell Ca 2+ responses varied. Overall, LTH attenuates Ca 2+ signaling while increasing the coupling of Ca 2+ sparks to BKCa activity; a process that potentially helps maintain oxygen delivery to the developing brain.

    Keywords: Smooth muscle, Calcium, Ca 2+ oscillation, Ca 2+ sparks, high altitude, hypoxia, ion channel

    Received: 12 Aug 2024; Accepted: 17 Oct 2024.

    Copyright: © 2024 Nelapudi, Boskind, Hu, Mallari, Chan, Wilson, Romero, Albert-Minckler, Zhang, Blood, Wilson, Puglisi and WILSON. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: SEAN M. WILSON, School of Medicine, Loma Linda University, Loma Linda, United States

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