{"doi":"10.1126/sciadv.ade8939","title":"Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation","abstract":"Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA -driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA -driven VMs.","journal":"Science Advances","year":2023,"id":331903,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":798851,"name":"Crescentia Cho","orcid":"0000-0003-4753-802X","position":1,"is_corresponding":false},{"id":997030,"name":"Hao Wang","orcid":"0000-0001-9976-9247","position":2,"is_corresponding":false},{"id":997637,"name":"Anne Hope Cooper","orcid":null,"position":3,"is_corresponding":false},{"id":663357,"name":"Elizabeth L. Doherty","orcid":"0000-0002-4793-2695","position":4,"is_corresponding":false},{"id":997031,"name":"David J. Rocco","orcid":"0000-0002-2580-1790","position":5,"is_corresponding":false},{"id":627748,"name":"Stephanie Huang","orcid":"0000-0003-2466-9174","position":6,"is_corresponding":false},{"id":997032,"name":"Sarah Kubik","orcid":"0000-0002-1699-1422","position":7,"is_corresponding":false},{"id":997033,"name":"Chloe P. Whitworth","orcid":"0000-0001-5726-6158","position":8,"is_corresponding":false},{"id":997034,"name":"Ryan T. Armstrong","orcid":"0000-0001-6431-7902","position":9,"is_corresponding":false},{"id":461235,"name":"Anthony J. Hickey","orcid":"0000-0002-3324-9326","position":10,"is_corresponding":false},{"id":281166,"name":"Boyce E. Griffith","orcid":"0000-0002-9800-7504","position":11,"is_corresponding":false},{"id":323196,"name":"Matthew L. Kutys","orcid":"0000-0002-0752-649X","position":12,"is_corresponding":false},{"id":997035,"name":"Julie Blatt","orcid":"0000-0002-7658-8096","position":13,"is_corresponding":false},{"id":282749,"name":"William J. Polacheck","orcid":"0000-0003-2728-0746","position":14,"is_corresponding":false},{"id":663358,"name":"Wen Yih Aw","orcid":"0000-0002-1724-412X","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T01:09:25.015646Z","pmid":"36791204","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":[]}