دورية أكاديمية
ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia.
| العنوان: | ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia. |
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| المؤلفون: | Zhou X; Cell and Molecular Biology Department, Tulane University, New Orleans (X.Z., J.C.P., A.P.G., N.L.J., S.M.M.)., Pucel JC; Cell and Molecular Biology Department, Tulane University, New Orleans (X.Z., J.C.P., A.P.G., N.L.J., S.M.M.)., Nomura-Kitabayashi A; Litwin-Zucker Alzheimer's Research Center, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY (A.N.-K., P.C., P.M.)., Chandakkar P; Litwin-Zucker Alzheimer's Research Center, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY (A.N.-K., P.C., P.M.)., Guidroz AP; Cell and Molecular Biology Department, Tulane University, New Orleans (X.Z., J.C.P., A.P.G., N.L.J., S.M.M.)., Jhangiani NL; Cell and Molecular Biology Department, Tulane University, New Orleans (X.Z., J.C.P., A.P.G., N.L.J., S.M.M.)., Bao D; Biochemistry and Molecular Biology Department, Tulane University School of Medicine, New Orleans, LA (D.B., J.F.)., Fan J; Biochemistry and Molecular Biology Department, Tulane University School of Medicine, New Orleans, LA (D.B., J.F.)., Arthur HM; Biosciences Institute, Center for Life, Newcastle University, United Kingdom (H.M.A.)., Ullmer C; Roche Innovation Center, Basel, Switzerland (C.U.)., Klein C; Roche Innovation Center, Zurich, Switzerland (C.K.)., Marambaud P; Litwin-Zucker Alzheimer's Research Center, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY (A.N.-K., P.C., P.M.).; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (P.M.)., Meadows SM; Cell and Molecular Biology Department, Tulane University, New Orleans (X.Z., J.C.P., A.P.G., N.L.J., S.M.M.).; Tulane Brain Institute, Tulane University, New Orleans, LA (S.M.M.). |
| المصدر: | Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2023 Aug; Vol. 43 (8), pp. 1384-1403. Date of Electronic Publication: 2023 Jun 08. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 9505803 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4636 (Electronic) Linking ISSN: 10795642 NLM ISO Abbreviation: Arterioscler Thromb Vasc Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins Original Publication: Dallas, TX : American Heart Association, c1995- |
| مواضيع طبية MeSH: | Telangiectasia, Hereditary Hemorrhagic*/drug therapy , Telangiectasia, Hereditary Hemorrhagic*/genetics , Arteriovenous Malformations*/metabolism, Animals ; Mice ; Endothelial Cells/metabolism ; Angiopoietin-2/genetics ; Angiopoietin-2/metabolism ; Phenotype |
| مستخلص: | Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT. Methods: Cerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods. Results: Comparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes. Conclusions: Elevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT. Competing Interests: Disclosures C. Ullmer and C. Klein declare employment, stock ownership and patents with Roche. |
| التعليقات: | Comment in: Arterioscler Thromb Vasc Biol. 2023 Aug;43(8):1404-1408. doi: 10.1161/ATVBAHA.123.319631. (PMID: 37345521) |
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| معلومات مُعتمدة: | 20PRE35120237 United States AHA American Heart Association-American Stroke Association; R01 HL150040 United States HL NHLBI NIH HHS; R01 HL139778 United States HL NHLBI NIH HHS; P30 DK114857 United States DK NIDDK NIH HHS; R01 HL139713 United States HL NHLBI NIH HHS; R01 HL163196 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: angiogenesis; angiopoietin; arteriovenous malformations; brain; endothelial |
| المشرفين على المادة: | 0 (Angiopoietin-2) |
| تواريخ الأحداث: | Date Created: 20230608 Date Completed: 20230728 Latest Revision: 20240802 |
| رمز التحديث: | 20240802 |
| مُعرف محوري في PubMed: | PMC10524982 |
| DOI: | 10.1161/ATVBAHA.123.319385 |
| PMID: | 37288572 |
| قاعدة البيانات: | MEDLINE |
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