{"doi":"10.1161/01.res.0000138952.16382.ad","title":"Chronic Hypoxia–Induced Upregulation of Store-Operated and Receptor-Operated Ca\n            <sup>2+</sup>\n            Channels in Pulmonary Arterial Smooth Muscle Cells","abstract":"<jats:p>\n            Chronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca\n            <jats:sup>2+</jats:sup>\n            homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca\n            <jats:sup>2+</jats:sup>\n            regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca\n            <jats:sup>2+</jats:sup>\n            entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or thapsigargin to deplete Ca\n            <jats:sup>2+</jats:sup>\n            stores, caused dramatic increase in cation entry measured by Mn\n            <jats:sup>2+</jats:sup>\n            quenching of fura-2 and by Ca\n            <jats:sup>2+</jats:sup>\n            transients. OAG-induced responses were ≈700-fold more resistant to La\n            <jats:sup>3+</jats:sup>\n            inhibition than thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca\n            <jats:sup>2+</jats:sup>\n            or inhibition of store-operated Ca\n            <jats:sup>2+</jats:sup>\n            entry with La\n            <jats:sup>3+</jats:sup>\n            and SK&amp;F-96365 reversed the elevated basal [Ca\n            <jats:sup>2+</jats:sup>\n            ]\n            <jats:sub>i</jats:sub>\n            in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.\n          </jats:p>","journal":"Circulation Research","year":2004,"id":26264,"datarank":10.995038695800371,"base_score":5.877735781779639,"endowment":5.877735781779639,"self_citation_contribution":0.881660367266946,"citation_network_contribution":10.113378328533425,"self_endowment_contribution":0.881660367266946,"citer_contribution":10.113378328533425,"corpus_percentile":null,"corpus_rank":null,"citation_count":356,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":152351,"name":"George P.H. Leung","orcid":null,"position":1,"is_corresponding":false},{"id":152352,"name":"Wei-Min Zhang","orcid":null,"position":2,"is_corresponding":false},{"id":152353,"name":"Xiao-Ru Yang","orcid":null,"position":3,"is_corresponding":false},{"id":152354,"name":"Kay-Pong Yip","orcid":null,"position":4,"is_corresponding":false},{"id":152355,"name":"Chung-Ming Tse","orcid":null,"position":5,"is_corresponding":false},{"id":152356,"name":"James S.K. Sham","orcid":null,"position":6,"is_corresponding":false},{"id":152350,"name":"Mo-Jun Lin","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.877735781779639,"endowment":5.877735781779639,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"15256480","pmcid":null,"openalex_id":"https://openalex.org/W2100577158","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"HL-071835","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"HL-075134","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"HL-063813","title":null}],"total_grants":3,"fwci":8.075,"citation_percentile":0.98431443,"influential_citations":34,"citation_trend":[{"year":2012,"count":20},{"year":2013,"count":26},{"year":2014,"count":18},{"year":2015,"count":24},{"year":2016,"count":23},{"year":2017,"count":15},{"year":2018,"count":18},{"year":2019,"count":8},{"year":2020,"count":12},{"year":2021,"count":15},{"year":2022,"count":10},{"year":2023,"count":5},{"year":2024,"count":7},{"year":2025,"count":4},{"year":2026,"count":5}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://www.ahajournals.org/doi/full/10.1161/01.RES.0000138952.16382.ad","host_type":"publisher"},{"url":"https://doi.org/10.1161/01.res.0000138952.16382.ad","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/15256480","host_type":"repository"},{"url":"http://hdl.handle.net/10722/80288","host_type":"repository"}],"fields_of_study":["Ion channel regulation and function","Ion Channels and Receptors","Neuroscience of respiration and sleep","Biology","Medicine","Environmental Science","Animals","Calcium","Calcium Channels","Cations","Cell Hypoxia","Cells, Cultured","Diglycerides","Hypertension, Pulmonary","Ion Transport","Male","Muscle, Smooth, Vascular","Pulmonary Artery","RNA Interference","Rats","Rats, Wistar","TRPC Cation Channels","Thapsigargin","Up-Regulation"],"mesh_terms":["Animals","Calcium","Cations","Cells, Cultured","Diglycerides","Hypertension, Pulmonary","Male","Muscle, Smooth, Vascular","Pulmonary Artery","Calcium Channels","Cell Hypoxia","Up-Regulation","Ion Transport","Rats, Wistar","Thapsigargin","RNA Interference","TRPC Cation Channels","Rats"],"keywords":["Downregulation and upregulation","Hypoxia (environmental)","Cardiology","Chemistry","Internal medicine","Medicine","Oxygen","Biochemistry","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-08T13:04:32.981476Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}