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Interestingly, ATP-induced endothelial Ca<jats:sup>2+<\/jats:sup>entry as well as membrane cholesterol (Chol) are decreased in pulmonary arteries from CH rats (4 wk, barometric pressure = 380 Torr) compared with normoxic controls. Store-operated Ca<jats:sup>2+<\/jats:sup>entry (SOCE) and depolarization-induced Ca<jats:sup>2+<\/jats:sup>entry are major components of the response to ATP and are similarly decreased after CH. We hypothesized that membrane Chol facilitates both SOCE and depolarization-induced pulmonary endothelial Ca<jats:sup>2+<\/jats:sup>entry and that CH attenuates these responses by decreasing membrane Chol. To test these hypotheses, we administered Chol or epicholesterol (Epichol) to acutely isolated pulmonary arterial endothelial cells (PAECs) from control and CH rats to either supplement or replace native Chol, respectively. The efficacy of membrane Chol manipulation was confirmed by filipin staining. Epichol greatly reduced ATP-induced Ca<jats:sup>2+<\/jats:sup>influx in PAECs from control rats. Whereas Epichol similarly blunted endothelial SOCE in PAECs from both groups, Chol supplementation restored diminished SOCE in PAECs from CH rats while having no effect in controls. Similar effects of Chol manipulation on PAEC Ca<jats:sup>2+<\/jats:sup>influx were observed in response to a depolarizing stimulus of KCl. Furthermore, KCl-induced Ca<jats:sup>2+<\/jats:sup>entry was inhibited by the T-type Ca<jats:sup>2+<\/jats:sup>channel antagonist mibefradil but not the L-type Ca<jats:sup>2+<\/jats:sup>channel inhibitor diltiazem. We conclude that PAEC membrane Chol is required for ATP-induced Ca<jats:sup>2+<\/jats:sup>entry and its two components, SOCE and depolarization-induced Ca<jats:sup>2+<\/jats:sup>entry, and that reduced Ca<jats:sup>2+<\/jats:sup>entry after CH may be due to loss of this key regulator.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY This research is the first to examine the direct role of membrane cholesterol in regulating pulmonary endothelial agonist-induced Ca<jats:sup>2+<\/jats:sup>entry and its components. The results provide a potential mechanism by which chronic hypoxia impairs pulmonary endothelial Ca<jats:sup>2+<\/jats:sup>influx, which may contribute to pulmonary hypertension.<\/jats:p>","DOI":"10.1152\/ajpheart.00097.2017","type":"journal-article","created":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:30:19Z","timestamp":1491006619000},"page":"H1176-H1184","source":"Crossref","is-referenced-by-count":17,"title":["Reduced membrane cholesterol limits pulmonary endothelial Ca<sup>2+<\/sup>entry after chronic hypoxia"],"prefix":"10.1152","volume":"312","author":[{"given":"Bojun","family":"Zhang","sequence":"first","affiliation":[{"name":"Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5725-4664","authenticated-orcid":false,"given":"Jay 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