title: Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation.
abstract: Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell-pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Huanjiao
authors.initials: H
authors.lastname: Jenny Zhou
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Department of Pharmacology, Yale University School of Medicine, New Haven, CT.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Tang
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Guangzhou Darron Medscience, Co. Ltd, Guangzhou, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Department of Toxicology, School of Public Health, Sun Yat-sen University of Medical Sciences, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liang
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zongren
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Department of Pharmacology, Yale University School of Medicine, New Haven, CT.
authors.forename: Qianying
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vortmeyer
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT.
authors.forename: Derek
authors.initials: D
authors.lastname: Toomre
authors.affiliation: Department of Antibody Engineering, Genentech Inc, South San Francisco, CA.
authors.forename: Germaine
authors.initials: G
authors.lastname: Fuh
authors.affiliation: Department of Molecular Oncology, Genentech Inc, South San Francisco, CA.
authors.forename: Minghong
authors.initials: M
authors.lastname: Yan
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Kluger
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Department of Pharmacology, Yale University School of Medicine, New Haven, CT.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT.|Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Guangzhou Darron Medscience, Co. Ltd, Guangzhou, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001921:Brain; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005089:Exocytosis; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D042787:Receptor, TIE-2 / Q000378:metabolism; D051040:Vesicle-Associated Membrane Protein 3
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C495390:PDCD10 protein, human; C559318:PDCD10 protein, mouse; D011518:Proto-Oncogene Proteins; C485549:Unc13b protein, mouse; D051040:Vesicle-Associated Membrane Protein 3; C494953:vesicle-associated membrane protein 3, mouse; D042787:Receptor, TIE-2