{"doi":"10.1172/jci139570","title":"Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation","abstract":"Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1α in astrocytes, resulting in increased VEGF production and expression of a \"hypoxic\" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.","journal":"Journal of Clinical Investigation","year":2021,"id":154669,"datarank":0.6238324625039509,"base_score":4.1588830833596715,"endowment":4.1588830833596715,"self_citation_contribution":0.6238324625039509,"citation_network_contribution":0.0,"self_endowment_contribution":0.6238324625039509,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":63,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"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":656101,"name":"Catherine Chinhchu Lai","orcid":null,"position":1,"is_corresponding":false},{"id":489972,"name":"Shady Soliman","orcid":"0000-0002-3670-8540","position":2,"is_corresponding":false},{"id":656102,"name":"Preston Hale","orcid":null,"position":3,"is_corresponding":false},{"id":337625,"name":"Angela Pham","orcid":"0000-0001-5982-7246","position":4,"is_corresponding":false},{"id":655255,"name":"Esau J. Estrada","orcid":"0000-0001-7949-4151","position":5,"is_corresponding":false},{"id":441415,"name":"Sara McCurdy","orcid":"0000-0001-7854-8808","position":6,"is_corresponding":false},{"id":313686,"name":"Romuald Girard","orcid":"0000-0002-5893-9315","position":7,"is_corresponding":false},{"id":655256,"name":"Riya Verma","orcid":"0000-0003-1795-1497","position":8,"is_corresponding":false},{"id":351072,"name":"Thomas Moore","orcid":"0000-0002-9540-2971","position":9,"is_corresponding":false},{"id":351073,"name":"Rhonda Lightle","orcid":"0000-0003-2760-195X","position":10,"is_corresponding":false},{"id":351074,"name":"Nicholas Hobson","orcid":"0000-0001-6034-8795","position":11,"is_corresponding":false},{"id":337379,"name":"Robert Shenkar","orcid":"0000-0002-1300-6845","position":12,"is_corresponding":false},{"id":229204,"name":"Orit Poulsen","orcid":null,"position":13,"is_corresponding":false},{"id":94986,"name":"Gabriel G. Haddad","orcid":"0000-0001-9043-3245","position":14,"is_corresponding":false},{"id":430147,"name":"Richard Daneman","orcid":"0000-0002-7749-6353","position":15,"is_corresponding":false},{"id":326214,"name":"Brendan Gongol","orcid":"0000-0001-9627-613X","position":16,"is_corresponding":false},{"id":288436,"name":"Hao Sun","orcid":"0000-0002-4790-8847","position":17,"is_corresponding":false},{"id":288433,"name":"Frédéric Lagarrigue","orcid":"0000-0002-4660-8666","position":18,"is_corresponding":false},{"id":313407,"name":"Issam A. Awad","orcid":"0000-0003-1510-602X","position":19,"is_corresponding":false},{"id":288441,"name":"Mark H. Ginsberg","orcid":"0000-0002-5685-5417","position":20,"is_corresponding":false},{"id":288439,"name":"Miguel Alejandro Lopez‐Ramirez","orcid":"0000-0001-7089-4060","position":0,"is_corresponding":true}],"reference_count":105,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:43:54.469024Z","pmid":"34043589","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":[]}