{"doi":"10.1101/2021.10.16.464653","title":"A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation","abstract":"Abstract Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the Pkd1 gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific Pkd1 knockout (Pkd1 ecKO) mice, we show that flow activates PC-1-mediated, Ca 2+ -dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and primarily via the activation of nitric oxide synthase (NOS), with a smaller contribution from small-conductance Ca 2+ -activated K + (SK) channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (Pkd2 ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (Pkd1/Pkd2 ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates non-selective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility and demonstrate that this occurs through the formation of an interdependent signaling complex with PC-2 in endothelial cells. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to Ca 2+ influx, NOS and SK channel activation, vasodilation and a reduction in blood pressure.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221822,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":822993,"name":"Miranda Floen","orcid":null,"position":1,"is_corresponding":false},{"id":353061,"name":"M. Dennis Leo","orcid":"0000-0002-2703-4011","position":2,"is_corresponding":false},{"id":353063,"name":"Raquibul Hasan","orcid":"0000-0002-6897-2901","position":3,"is_corresponding":false},{"id":353062,"name":"Carlos Fernández‐Peña","orcid":"0000-0002-0726-3204","position":4,"is_corresponding":false},{"id":432778,"name":"Purnima Singh","orcid":"0000-0002-0675-9128","position":5,"is_corresponding":false},{"id":399783,"name":"Kafait U. Malik","orcid":"0000-0001-9157-0356","position":6,"is_corresponding":false},{"id":353069,"name":"Jonathan H. Jaggar","orcid":"0000-0003-1505-3335","position":7,"is_corresponding":false},{"id":353060,"name":"Charles Mackay","orcid":"0000-0002-2875-0677","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:53:59.302331Z","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,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}