{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:17:35Z","timestamp":1753892255641,"version":"3.41.2"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T00:00:00Z","timestamp":1730764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL149608 R01HL155295"],"award-info":[{"award-number":["R01HL149608 R01HL155295"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000076","name":"Directorate for Biological Sciences","doi-asserted-by":"publisher","award":["0923559"],"award-info":[{"award-number":["0923559"]}],"id":[{"id":"10.13039\/100000076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>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<jats:sup>2+<\/jats:sup> in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca<jats:sup>2+<\/jats:sup> 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<jats:sup>2+<\/jats:sup> sparks and whole-cell Ca<jats:sup>2+<\/jats:sup> signals and coupling with BK<jats:sub>Ca<\/jats:sub> channel activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Confocal imaging of cytosolic Ca<jats:sup>2+<\/jats:sup> and recording BK<jats:sub>Ca<\/jats:sub> currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (\u223c140 days of gestation) from ewes held at low- (700 m) and high-altitude (3,801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 \u03bcM ryanodine (Ry), to block RyR mediated Ca<jats:sup>2+<\/jats:sup> release.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Membrane depolarization increased Ry-sensitive Ca<jats:sup>2+<\/jats:sup> spark frequency in normoxic and LTH groups along with BK<jats:sub>Ca<\/jats:sub> activity. LTH reduced Ca<jats:sup>2+<\/jats:sup> spark and whole-cell Ca<jats:sup>2+<\/jats:sup> activity and induced a large leftward shift in the voltage-dependence of BK<jats:sub>Ca<\/jats:sub> current activation. The influence of LTH on the spatial and temporal aspects of Ca<jats:sup>2+<\/jats:sup> sparks and whole-cell Ca<jats:sup>2+<\/jats:sup> responses varied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Overall, LTH attenuates Ca<jats:sup>2+<\/jats:sup> signaling while increasing the coupling of Ca<jats:sup>2+<\/jats:sup> sparks to BK<jats:sub>Ca<\/jats:sub> activity; a process that potentially helps maintain oxygen delivery to the developing brain.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphys.2024.1479882","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T06:12:00Z","timestamp":1730787120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Long-term hypoxia modulates depolarization activation of BKCa currents in fetal sheep middle cerebral arterial myocytes"],"prefix":"10.3389","volume":"15","author":[{"given":"Nikitha","family":"Nelapudi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison","family":"Boskind","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-Qun","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Mallari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eris","family":"Albert-Minckler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lubo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arlin B.","family":"Blood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher G.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Luis","family":"Puglisi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean M.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1097\/FJC.0000000000000192","article-title":"Role of the sympathetic autonomic nervous system in hypoxic remodeling of the fetal cerebral vasculature","volume":"65","author":"Adeoye","year":"2015","journal-title":"J. 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