{"doi":"10.1101/2022.10.08.511300","title":"Hyperactive mTOR in Lung Mesenchyme Induces Endothelial Dysfunction and Pulmonary Vascular Remodeling","abstract":"Abstract Pulmonary vascular remodeling is the key structural abnormality in pulmonary hypertension (PH). Mechanistic target of rapamycin (mTOR) has long been suspected to play a role in the development of pulmonary vascular remodeling. However, underlying cellular and molecular mechanisms leading to this pathophysiological condition remain incompletely understood. To elucidate the crosstalk between lung mesenchyme with activated mTOR and endothelial cells (ECs), we focused on a monogenic lung disease, pulmonary lymphangioleiomyomatosis (LAM). LAM is a progressive cystic lung disease caused by a mutational inactivation of tuberous sclerosis complex (TSC1/TSC2), which results in constitutive mTOR activation in mesenchymal LAM cells. ECs derived from LAM lung explants showed increased proliferation, migration, and defective angiogenesis compared to age- and sex-matched ECs from control human lung. In LAM cells, we found increased WNT2 ligand expression. We also identified corresponding Frizzled 4 (FZD) receptors on ECs isolated from distal LAM lung, suggesting cellular crosstalk between LAM cells and ECs. In endothelial-fibroblast cocultures, treatment of normal ECs with WNT2 ligands recapitulated LAM EC phenotype and morphology. We observed transcriptomic upregulation in metabolic, angiogenic and growth pathways in ECs of young mice, while 1-year-old Tsc2 KO mice spontaneously developed pulmonary vascular remodeling with concurrent elevation in right ventricular systolic pressure. Our study demonstrates that LAM cells are not just a pathological mesenchymal cell state but a signaling hub that contributes to dysregulated cellular response in the surrounding vasculature, eventual pulmonary vascular remodeling and PH.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":312251,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":323518,"name":"Ryan W. Rue","orcid":"0009-0004-1608-9780","position":1,"is_corresponding":false},{"id":1010234,"name":"Akansha Goel","orcid":null,"position":2,"is_corresponding":false},{"id":323517,"name":"Kseniya Obraztsova","orcid":"0000-0002-8573-7401","position":3,"is_corresponding":false},{"id":323520,"name":"Alexander R. Mukhitov","orcid":"0000-0001-6443-0788","position":4,"is_corresponding":false},{"id":1009684,"name":"Kanth Swaroop Vanka","orcid":"0000-0003-3641-2499","position":5,"is_corresponding":false},{"id":1009685,"name":"Carly J. Smith","orcid":"0000-0003-3755-6785","position":6,"is_corresponding":false},{"id":228725,"name":"Maria C. Basil","orcid":"0000-0003-4716-1285","position":7,"is_corresponding":false},{"id":266253,"name":"Laura T. Ferguson","orcid":"0000-0001-9979-4768","position":8,"is_corresponding":false},{"id":840083,"name":"Joseph D. Planer","orcid":"0000-0002-1507-7735","position":9,"is_corresponding":false},{"id":260644,"name":"Edward Cantu","orcid":"0000-0003-1105-0129","position":10,"is_corresponding":false},{"id":848156,"name":"Grażyna Kwapiszewska","orcid":"0000-0003-0518-9079","position":11,"is_corresponding":false},{"id":228733,"name":"Edward E. Morrisey","orcid":"0000-0001-5785-1939","position":12,"is_corresponding":false},{"id":158200,"name":"Jillian F. Evans","orcid":null,"position":13,"is_corresponding":false},{"id":323524,"name":"Vera P. Krymskaya","orcid":"0000-0002-0584-4486","position":14,"is_corresponding":false},{"id":323519,"name":"Susan M. Lin","orcid":"0000-0002-2415-8350","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T00:33:36.072096Z","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":[]}