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Angiopoietin-2: An Emerging Tie to Pathological Vessel Enlargement

2021; Lippincott Williams & Wilkins; Volume: 42; Issue: 1 Linguagem: Inglês

10.1161/atvbaha.121.317102

1524-4636

Negar Khosraviani, Ruilin Wu, Jason E. Fish,

Lymphatic System and Diseases

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 42, No. 1Angiopoietin-2: An Emerging Tie to Pathological Vessel Enlargement Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBAngiopoietin-2: An Emerging Tie to Pathological Vessel Enlargement Negar Khosraviani, Ruilin Wu and Jason E. Fish Negar KhosravianiNegar Khosraviani Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada (N.K., R.W., J.E.F.). Toronto General Hospital Research Institute (N.K., R.W., J.E.F.), University Health Network, Ontario, Canada. , Ruilin WuRuilin Wu Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada (N.K., R.W., J.E.F.). Toronto General Hospital Research Institute (N.K., R.W., J.E.F.), University Health Network, Ontario, Canada. and Jason E. FishJason E. Fish Correspondence to: Jason E. Fish, PhD, Toronto General Hospital Research Institute, University Health Network, 101 College St, 3-309 Princess Margaret Cancer Research Tower, Toronto, Ontario, Canada, M5G 1L7. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0640-7277 Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada (N.K., R.W., J.E.F.). Toronto General Hospital Research Institute (N.K., R.W., J.E.F.), University Health Network, Ontario, Canada. Peter Munk Cardiac Centre (J.E.F.), University Health Network, Ontario, Canada. Originally published11 Nov 2021https://doi.org/10.1161/ATVBAHA.121.317102Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:3–5is related toEndothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood VesselsOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 11, 2021: Ahead of Print Dynamic hierarchical vascular networks are requisite for tissue homeostasis and are formed and maintained by highly interconnected signaling pathways. A wide range of vascular malformations—including arteriovenous, cavernous, venous, lymphatic, and capillary malformations—occur due to mutations in genes encoding signaling components that act to control endothelial cell (EC) behavior. In the case of sporadic disease, these are typically the result of somatic mutations within ECs. The clonal expansion of mutated cells drives altered vessel morphology, including lumen enlargement—a characteristic feature of malformed vessels. By identifying mutant genes and characterizing downstream pathways, novel therapeutic approaches can be discovered for these vascular lesions, which are notoriously difficult to treat. In this issue of ATVB, Huang et al1 identify ANGPT2 (angiopoietin-2) as a regulator of vessel enlargement in a mouse xenograft model of capillary malformation (CM) in which endothelial colony forming cells express GNAQ p.R183Q, the most common somatic mutation in CM. This exciting discovery opens up new possibilities for therapeutic intervention for vascular malformations.See accompanying article on page e27Cutaneous CM, also known as port-wine stain, affects 0.3% of infants and is associated with Sturge-Weber syndrome, a rare neurocutaneous disorder. CM is a slow-flow vascular anomaly characterized by clusters of abnormal capillaries and venules that are enlarged, have enhanced sprouting, and abnormal pericyte coverage.2 The occurrence of cutaneous and brain CMs has been linked primarily to somatic missense mutation in GNAQ (p. R183Q), an alpha subunit of the heterotrimeric G protein complex, Gαq. This gain-of-function mutation occurs in the conserved GTP-binding pocket that mediates the hydrolysis of GTP to GDP, resulting in constitutive activity.3 This somatic mutation occurs predominantly in ECs of brain and skin CMs at a low allele frequency but is also present in some surrounding stromal cells.4,5By characterizing pathways downstream of activated GNAQ, Huang et al reveal a critical role for phospholipase C β3 and identify a bifurcation of signaling pathways that result in activation of PKC-NFκB-ANGPT2 and calcineurin-NFATc1-DSCR1.41 (Figure). The increased expression of ANGPT2 and DSCR1.4 were further confirmed in mouse xenograft studies and human CM tissues. Importantly, GNAQ p.R183Q expression in endothelial colony forming cells was sufficient to induce the formation of enlarged CM-like vessels, and ANGPT2 inhibition prevented pathological vessel enlargement, positioning ANGPT2 as a promising therapeutic target.Download figureDownload PowerPointFigure. GNAQ mutations drive ANGPT2-dependent vessel enlargement. Left, Schematic of the molecular pathway identified by Huang et al. Activating mutations in GNAQ (p.R183Q) drive PLCβ3 (phospholipase C β3) signaling and conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol phosphate (IP3) and diacylglyceride (DAG). Calcineurin activation leads to the nuclear translocation of NFATc1 (nuclear factor of activated T cells-1) and induction of Down Syndrome critical region gene 1.4 (DSCR1.4). PKC (protein kinase C) signaling leads to the nuclear translation of NFκB (nuclear factor κ-light chain enhancer of activated B-cells) and induction of Angiopoietin-2 (ANGPT2). Right, Secretion of ANGPT2 drives pathological vessel enlargement. The figure was created with Biorender.com.Angiopoietins regulate multiple aspects of vascular biology through their interaction with the TIE2 receptor on ECs. ANGPT1 is highly expressed in adult tissue and promotes vascular maturation and maintains vascular stability.6,7 Conversely, ANGPT2 destabilizes vessels and promotes angiogenesis through antagonism of ANGPT1.6 However, ANGPT2 action is highly context dependent and treatment with ANGPT2 mimic can also activate TIE2 to mediate vessel enlargement.8 Notably, ANGPT2 has been implicated in the pathogenesis of several distinct vascular malformations, where the aberrant elevation of ANGPT2 contributes to enlargement of vessels and morphological changes. For example, ANGPT2 is elevated in patient tissue from brain arteriovenous malformations.9 In cerebral cavernous malformation, loss of CCM3 (cerebral cavernous malformation 3) results in exocytosis of ANGPT2, contributing to disrupted EC junctions, enlargement of lumens, and defective pericyte recruitment.10 Consistent with these observations, EC-specific SMAD4-deficient mice, modeling hereditary hemorrhagic telangiectasia, also have robust ANGPT2 elevation.11 Inhibition of ANGPT2 function through knockdown or the use of inhibitors, restored normal EC shape and size and reduced vessel diameter.11 Collectively, these studies reveal that ANGPT2 induction is a unifying characteristic of vascular malformations with distinct causes, and that ANGPT2 is a potent mediator of vessel enlargement.Aberrant lumen expansion plays an important role in the progression of malformations as it significantly alters blood flow and local hemodynamics. Yet, the underlying molecular mechanisms responsible for the development of enlarged vessels remains an open question. Expanded lumens can be due to increases in the number or size/morphology of ECs. It is unclear which of these processes is involved in lumen expansion in the xenograft model used by Huang et al, although the decrease in vascular density in the xenograft model may suggest the latter. Interestingly, in the setting of hemorrhagic telangiectasia, vessel enlargement involves ECs becoming larger and not elongating properly in response to laminar flow.12,13 Regarding CM, Gαq has been implicated in flow sensing,14,15 but the impact of the R183Q mutation in this context has not been assessed. It will be of interest to determine whether ANGPT2 is involved in regulating EC hemodynamic responses in the setting of CM and other malformations. Notably, ANGPT2 is known to be a flow-responsive gene and ANGPT2 regulates phenotypes that are dependent on hemodynamics.16 Determining whether ANGPT2 influences cell-cell or cell-ECM adhesion, modulates pericyte recruitment or if ANGPT2 secretion affects the phenotype of wild-type cells within the lesion, should also be pursued. Aside from antagonizing ANGPT1/TIE2 signaling, ANGPT2 can bind to integrins to activate signaling through the FAK-RAC1 pathway to modulate cytoskeletal rearrangements, cell migration, and angiogenesis.17,18 Thus, ANGPT2-dependent cytoskeleton changes at the cellular level may lead to altered vascular organization and the development of enlarged vessels in CM. Further investigations are needed to determine whether ANGPT2 acts in a TIE2-dependent or -independent manner in CM.Another intriguing aspect of the Huang et al study is the concurrent activation of both angiogenic and inflammatory pathways downstream of GNAQ p.R183Q.1 ANGPT2 is known to regulate both inflammation and angiogenesis.19 The extent to which angiogenic and inflammatory pathways contribute to CM pathogenesis remains to be uncovered, but inflammation has been postulated to participate in other vascular malformations through the modulation of the microenvironment.20ANGPT2, initially characterized as an antagonistic ligand to ANGPT1, has been shown to be involved in multiple aspects of endothelial biology. It is currently being explored as a therapeutic target in multiple diseases, including sepsis and cancer.21 As such, it is exciting that ANGPT2 inhibition can prevent vessel enlargement in animal models of CM and other vascular malformations—a critical disease phenotype. In future studies, it will be important to determine whether ANGPT2 acts to initiate and maintain CM phenotypes to elucidate whether ANGPT2 antagonism would be an effective treatment in CM patients with established vascular pathologies.Article InformationSources of FundingN. Khosraviani is supported by an Ontario Graduate Studentship. R. Wu is supported by a Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR). J.E. Fish is supported by a Canada Research Chair from CIHR and his lab received infrastructure funding from the Canada Foundation for Innovation, the John R. Evans Leaders Fund and the Ontario Research Fund. Vascular malformation research in the Fish laboratory is supported by a Project Grant from CIHR (PJT 155922) and the US Department of Defense (W81XWH-18-1-0351).Disclosures None.Footnotes*N. Khosraviani and R. Wu contributed equally.For Sources of Funding and Disclosures, see page 5.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Jason E. Fish, PhD, Toronto General Hospital Research Institute, University Health Network, 101 College St, 3-309 Princess Margaret Cancer Research Tower, Toronto, Ontario, Canada, M5G 1L7. Email jason.[email protected]caReferences1. Huang L, Bichsel C, Norris AL, Thorpe J, Pevsner J, Alexandrescu S, Pinto A, Zurakowski D, Kleiman RJ, Sahin M, et al.. Endothelial GNAQ p.R183Q increases ANGPT2 (angiopoietin-2) and drives formation of enlarged blood vessels.Arterioscler Thromb Vasc Biol. 2022; 42:e27–e43. doi: 10.1161/ATVBAHA.121.316651LinkGoogle Scholar2. Bichsel C, Bischoff J. A somatic missense mutation in GNAQ causes capillary malformation.Curr Opin Hematol. 2019; 26:179–184. doi: 10.1097/MOH.0000000000000500CrossrefMedlineGoogle Scholar3. Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.N Engl J Med. 2013; 368:1971–1979. doi: 10.1056/NEJMoa1213507CrossrefMedlineGoogle Scholar4. Couto JA, Huang L, Vivero MP, Kamitaki N, Maclellan RA, Mulliken JB, Bischoff J, Warman ML, Greene AK. Endothelial cells from capillary malformations are enriched for somatic GNAQ mutations.Plast Reconstr Surg. 2016; 137:77e–82e. doi: 10.1097/PRS.0000000000001868CrossrefMedlineGoogle Scholar5. Huang L, Couto JA, Pinto A, Alexandrescu S, Madsen JR, Greene AK, Sahin M, Bischoff J. Somatic GNAQ mutation is enriched in brain endothelial cells in Sturge-Weber syndrome.Pediatr Neurol. 2017; 67:59–63. doi: 10.1016/j.pediatrneurol.2016.10.010CrossrefMedlineGoogle Scholar6. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, et al.. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.Science. 1997; 277:55–60. doi: 10.1126/science.277.5322.55CrossrefMedlineGoogle Scholar7. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis.Cell. 1996; 87:1171–1180. doi: 10.1016/s0092-8674(00)81813-9CrossrefMedlineGoogle Scholar8. Kim M, Allen B, Korhonen EA, Nitschké M, Yang HW, Baluk P, Saharinen P, Alitalo K, Daly C, Thurston G, et al.. Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation.J Clin Invest. 2016; 126:3511–3525. doi: 10.1172/JCI84871CrossrefMedlineGoogle Scholar9. Hashimoto T, Lam T, Boudreau NJ, Bollen AW, Lawton MT, Young WL. Abnormal balance in the angiopoietin-tie2 system in human brain arteriovenous malformations.Circ Res. 2001; 89:111–113. doi: 10.1161/hh1401.094281LinkGoogle Scholar10. Jenny Zhou H, Qin L, Zhang H, Tang W, Ji W, He Y, Liang X, Wang Z, Yuan Q, Vortmeyer A, et al.. Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation.Nat Med. 2016; 22:1033–1042. doi: 10.1038/nm.4169CrossrefMedlineGoogle Scholar11. Crist AM, Zhou X, Garai J, Lee AR, Thoele J, Ullmer C, Klein C, Zabaleta J, Meadows SM. Angiopoietin-2 inhibition rescues arteriovenous malformation in a smad4 hereditary hemorrhagic telangiectasia mouse model.Circulation. 2019; 139:2049–2063. doi: 10.1161/CIRCULATIONAHA.118.036952LinkGoogle Scholar12. Crist AM, Lee AR, Patel NR, Westhoff DE, Meadows SM. Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia.Angiogenesis. 2018; 21:363–380. doi: 10.1007/s10456-018-9602-0CrossrefMedlineGoogle Scholar13. Sugden WW, Meissner R, Aegerter-Wilmsen T, Tsaryk R, Leonard EV, Bussmann J, Hamm MJ, Herzog W, Jin Y, Jakobsson L, et al.. Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues.Nat Cell Biol. 2017; 19:653–665. doi: 10.1038/ncb3528CrossrefMedlineGoogle Scholar14. Albarrán-Juárez J, Iring A, Wang S, Joseph S, Grimm M, Strilic B, Wettschureck N, Althoff TF, Offermanns S. Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation.J Exp Med. 2018; 215:2655–2672. doi: 10.1084/jem.20180483CrossrefMedlineGoogle Scholar15. Dela Paz NG, Melchior B, Frangos JA. Shear stress induces Gαq/11 activation independently of G protein-coupled receptor activation in endothelial cells.Am J Physiol Cell Physiol. 2017; 312:C428–C437. doi: 10.1152/ajpcell.00148.2016CrossrefMedlineGoogle Scholar16. Tressel SL, Huang RP, Tomsen N, Jo H. Laminar shear inhibits tubule formation and migration of endothelial cells by an angiopoietin-2 dependent mechanism.Arterioscler Thromb Vasc Biol. 2007; 27:2150–2156. doi: 10.1161/ATVBAHA.107.150920LinkGoogle Scholar17. Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos EK, et al.. Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling.J Clin Invest. 2012; 122:1991–2005. doi: 10.1172/JCI58832CrossrefMedlineGoogle Scholar18. Hakanpaa L, Sipila T, Leppanen VM, Gautam P, Nurmi H, Jacquemet G, Eklund L, Ivaska J, Alitalo K, Saharinen P. Endothelial destabilization by angiopoietin-2 via integrin β1 activation.Nat Commun. 2015; 6:5962. doi: 10.1038/ncomms6962CrossrefMedlineGoogle Scholar19. Scholz A, Plate KH, Reiss Y. Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation.Ann NY Acad Sci. 2015; 1347:45–51. doi: 10.1111/nyas.12726CrossrefMedlineGoogle Scholar20. Mouchtouris N, Jabbour PM, Starke RM, Hasan DM, Zanaty M, Theofanis T, Ding D, Tjoumakaris SI, Dumont AS, Ghobrial GM, et al.. Biology of cerebral arteriovenous malformations with a focus on inflammation.J Cereb Blood Flow Metab. 2015; 35:167–175. doi: 10.1038/jcbfm.2014.179CrossrefMedlineGoogle Scholar21. Akwii RG, Sajib MS, Zahra FT, Mikelis CM. Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology.Cells. 2019; 8:E471. doi: 10.3390/cells8050471CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEndothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood VesselsLan Huang, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:e27-e43 January 2022Vol 42, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.121.317102PMID: 34758631 Originally publishedNovember 11, 2021 KeywordsEditorialsangiopoietin-2capillary malformationsomatic mutationGNAQvessel enlargementPDF download Advertisement