{"doi":"10.1172/jci.insight.155010","title":"Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress–related AMPK/FoxO1 signaling","abstract":"Angiopoietin-2 (Ang-2) is a key mediator of vascular disease during sepsis, and elevated plasma levels of Ang-2 are associated with organ injury scores and poor clinical outcomes. We have previously observed that biomarkers of endothelial glycocalyx (EG) damage correlate with plasma Ang-2 levels, suggesting a potential mechanistic linkage between EG injury and Ang-2 expression during states of systemic inflammation. However, the cell signaling mechanisms regulating Ang-2 expression following EG damage are unknown. In the current study, we determined the temporal associations between plasma heparan sulfate (HS) levels as a marker of EG erosion and plasma Ang-2 levels in children with sepsis and in mouse models of sepsis. Second, we evaluated the role of shear stress-mediated 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling in Ang-2 expression following enzymatic HS cleavage from the surface of human primary lung microvascular endothelial cells (HLMVECs). We found that plasma HS levels peaked before plasma Ang-2 levels in children and mice with sepsis. Further, we discovered that impaired AMPK signaling contributed to increased Ang-2 expression following HS cleavage from flow-conditioned HLMVECs, establishing a paradigm by which Ang-2 may be upregulated during sepsis.","journal":"JCI Insight","year":2022,"id":240986,"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":43,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"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":869558,"name":"Amit R. Ashtekar","orcid":null,"position":1,"is_corresponding":false},{"id":869148,"name":"Lei Zheng","orcid":"0000-0002-3684-6548","position":2,"is_corresponding":false},{"id":455434,"name":"Daniëlle Pretorius","orcid":"0000-0001-8658-2483","position":3,"is_corresponding":false},{"id":298154,"name":"Kaushlendra Tripathi","orcid":"0000-0002-3578-2917","position":4,"is_corresponding":false},{"id":61743,"name":"Ralph D. Sanderson","orcid":"0000-0003-2687-3363","position":5,"is_corresponding":false},{"id":393271,"name":"Amit Gaggar","orcid":"0000-0003-1586-5632","position":6,"is_corresponding":false},{"id":298152,"name":"Jillian R. Richter","orcid":"0000-0002-2233-1711","position":7,"is_corresponding":false},{"id":298153,"name":"Robert P. Richter","orcid":"0000-0002-3753-1994","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T00:22:51.435773Z","pmid":"35763350","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":[]}