Vascular Endothelial Growth Factor and Angiogenesis
2013; Lippincott Williams & Wilkins; Volume: 127; Issue: 16 Linguagem: Inglês
10.1161/circulationaha.113.002336
ISSN1524-4539
Autores Tópico(s)Apelin-related biomedical research
ResumoHomeCirculationVol. 127, No. 16Vascular Endothelial Growth Factor and Angiogenesis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBVascular Endothelial Growth Factor and AngiogenesisThe Xbp1 Games Jean-Sébastien Silvestre, PhD Jean-Sébastien SilvestreJean-Sébastien Silvestre From INSERM UMR-S 970, Paris Cardiovascular Research Center, Université Paris Descartes, Paris, France. Originally published25 Mar 2013https://doi.org/10.1161/CIRCULATIONAHA.113.002336Circulation. 2013;127:1644–1646Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 23, 2013: Previous Version 1 After the occlusion of a nutritive blood vessel, muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the fate of the ischemic tissue. During the latter phase of tissue healing, the different processes involved in new vessel formation, including angiogenesis, take place and represent an integral component of tissue remodeling, which controls the extent of ischemic injury. Angiogenesis is a complex process requiring the coordinated regulation of many activating and inhibitory pathways in which vascular endothelial growth factor (VEGF)–mediated endothelial cell (EC) migration and proliferation play an important role. VEGF acts, at least in part, through interaction with its VEGF receptor 2, also known as kinase insert domain receptor (KDR) in human or fetal liver kinase 1 (Flk1) in murine. Although the signaling pathways downstream of VEGF-mediated KDR/Flk1 activation have been analyzed in detail, the precise complex biology of this receptor has yet to be defined.Article see p 1712The X-box binding protein 1 (XBP1) exists as unspliced (XBP1u) and spliced (XBP1s) forms via the action of inositol-requiring enzyme 1α (IRE1α)–mediated unconventional splicing, in which XBP1u facilitates the recruitment of XBP1 mRNA cotranslationally.1 In addition, XBP1s protein level is downregulated by XBP1u through proteasome-mediated degradation.2 XBP1, a stress-inducible transcription factor, constitutes a key signal transducer in the endoplasmic reticulum (ER) stress response. The ER has emerged as a major site of cellular homeostasis, particularly for the unfolded protein response, which has been shown to play a major role in cancer and many other diseases. XBP1 has been identified as a target of ATF6, a major sensor and transducer protein on the ER membrane, leading to unconventional mRNA splicing and production of XBP1s, which can activate the unfolded protein response efficiently.1 Alternatively, XBP1s can act independently of its role in the ER stress response and is, for example, able to interact with the Forkhead box O1 transcription factor, leading to its proteasome-mediated degradation without improving the ER folding capacity.3In a very elegant study in this issue of Circulation, Zeng et al showed, for the first time, that VEGF activates XBP1 mRNA splicing in ECs through interaction of the C-terminal domain of KDR/Flk1 with IRE1α. XBP1s then regulates AKT/GSK/β-catenin/E2F2 signal pathway, leading to EC proliferation4 (Figure). Knockdown of XBP1 or IRE1α reduces VEGF-induced EC proliferation, and global deletion of XBP1 decreases the number of vessels in XBP1-deficient embryos, in part as a result of a reduced number of CD31+ and Flk1+ cells. Furthermore, endothelium-specific deletion of XBP1 (XBP1ecko) abrogates both retinal vasculogenesis and postischemic angiogenesis in mice with surgically induced hind-limb ischemia.4 In this pathological setting, it is noteworthy that whereas reconstitution of XBP1 via adenovirus-mediated XBP1s gene transfer improves foot perfusion in XBP1ecko animals, administration of VEGF-A is unable to restore tissue perfusion in ischemic legs of XBP1ecko animals, suggesting that functional XBP1 in ECs is essential for both basal and VEGF-A–induced tissue perfusion recovery in ischemic tissues. This striking observation suggests that XBP1 may be involved in additional molecular and cellular pathways governing postischemic revascularization. Tissue reperfusion after ischemia is controlled by arteriogenesis, the appearance of new arteriolar structures, and collateral growth, the development and remodeling of preexisting arteriolar anastomoses. Both are characterized by proliferation of smooth muscle cells and production of the extracellular matrix within the vascular wall. Interestingly, a decrease in smooth muscle cells is also observed in ischemic tissue of XBP1ecko animals, suggesting that XBP1 may be involved in an interaction between ECs and smooth muscle cells. It is also likely that XBP1 is involved in VEGF-independent effects. Indeed, the authors showed that conditioned medium from nontargeted lentivirus-treated ECs could rescue proliferation of XBP1 knockdown of ECs, suggesting that soluble factors secreted by ECs may control EC proliferation in the absence of VEGF.Download figureDownload PowerPointFigure. The X-box binding protein 1 (XBP1) games in angiogenesis. Vascular endothelial growth factor (VEGF)-A can activate XBP1 mRNA splicing through kinase insert domain receptor (KDR) interaction with unspliced XBP1 (XBP1u) and inositol-requiring enzyme 1α (IRE1α). The spliced XBP1 (XBP1s) regulates the Akt/GSK/β-catenin/E2F2 signal pathway, leading to endothelial cell proliferation. Knockdown of KDR abolishes the expression of C/EBP homologous protein-10 (CHOP-10). CHOP-10 is expressed at low levels under physiological conditions but is strongly induced at the transcription level in response to major sensor and transducer proteins on the endoplasmic reticulum membrane such as IRE1, ATF6, and PERK. CHOP-10 is a transcription factor shown to inhibit the expression of the proangiogenic endothelial nitric oxide synthase (eNOS). XBP1 may also be involved in endothelial cell and smooth muscle cell interaction and likely in the control of the immunoinflammatory reaction, both of which may participate in the overall effect of XBP1 on postischemic revascularization.Alternatively, it has been shown that cellular components of the inflammatory system play a critical role in this setting.5 Hence, numerous studies have demonstrated the importance of lymphocyte and monocyte recruitment in stimulating vessel growth and remodeling in ischemic tissue,6–11 including Tie-2–positive myeloid cells. Indeed, the authors used Tie2Cre mouse to generate XBP1ecko animals, and it is conceivable that hematopoietic cells contribute to the XBP1-deficient phenotype. Of note, it was shown that transplantation of bone marrow–derived cells isolated from XBP1ecko animals display reduced foot perfusion compared to transplantation of wild-type bone marrow-derived cells. These data suggest that XBP1 can directly or indirectly control bone marrow–derived inflammatory cell mobilization or recruitment to ischemic tissues and subsequently may affect postischemic revascularization.The IRE1α/XBP1 pathway is one of the multiple signal pathways activated by ER stress response. Interestingly, as revealed by this study, VEGF treatment does not activate other major sensor and transducer proteins on the ER membrane such as ATF6 and PERK.12 However, knockdown of KDR by siRNAs abolished VEGF-induced IRE1α phosphorylation, XBP1 splicing, and expression of C/EBP homologous protein-10 (CHOP-10). CHOP-10 is expressed at low levels under physiological conditions but is strongly induced at the transcription level in response to IRE1, ATF6, and PERK.12 CHOP-10 is a significant mediator of apoptosis, and it has recently been shown to control angiogenesis. Endothelial nitric oxide synthase (eNOS) mRNA and protein levels are significantly upregulated in CHOP-10–deficient human ECs, whereas overexpression of CHOP-10 inhibits basal transcriptional activation of the eNOS promoter. Interestingly, postischemic revascularization is increased in CHOP-10−/− mice with surgically induced hind-limb ischemia, and this effect is fully blunted in CHOP-10/eNOS double-knockout animals.13 In this regard, it should be noted that overexpression of XBP1s increases AKT phosphorylation, whereas knockdown of XBP1 or IRE1α attenuates the VEGF-induced AKT phosphorylation. The phosphorylation of eNOS by AKT represents a major Ca2+-independent regulatory mechanism for the activation of eNOS.14 Thus, it is plausible that the activation of eNOS signaling participates in the XBP1-induced increase in tissue perfusion. Hence, one cannot exclude the possibility that VEGF-induced IRE1α phosphorylation may activate the XBP1 proangiogenic pathway and the CHOP-10 angiostatic signaling. Hence, regulation of both XBP1 and CHOP-10 in the setting of ischemia may be part of an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to pathological stress.Finally, although the specific targets of XBP1s remain to be fully identified, the results of this very interesting study by Zeng et al highlight the concept that XBP1 can function in growth factor signal pathways, regulating angiogenesis and tissue perfusion, and may therefore be involved in other ischemic settings such as stroke or myocardial infarction. In support of this hypothesis, transient cerebral ischemia has been shown to activate XBP1 mRNA splicing, which protects cells from ischemia/reperfusion–induced damage.15 Hence, XBP1 may serve as putative target for novel therapeutic strategies in patients with ischemic cardiovascular diseases.Sources of FundingDr Silvestre is supported by grants from Institut National de la Santé et de la Recherche Médicale, Paris Descartes University, ANR Chemrepair (2010 BLAN 1127 02), Fondation Leducq transatlantic network (09-CVD-01), and Fondation pour la Recherche Médicale. Dr Silvestre is a recipient of a Contrat d'Interface from Assistance Publique-Hôpitaux de Paris.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jean-Sébastien Silvestre, PhD, Paris Cardiovascular Research Center, INSERM U970, Université Paris Descartes, 56 Rue Leblanc, 75015 Paris, France. E-mail [email protected]References1. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.Cell. 2001; 107:881–891.CrossrefMedlineGoogle Scholar2. Yoshida H, Oku M, Suzuki M, Mori K. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response.J Cell Biol. 2006; 172:565–575.CrossrefMedlineGoogle Scholar3. Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Lee J, Fisher SJ, White MF, Biddinger SB, Ozcan U. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction.Nat Med. 2011; 17:356–365.CrossrefMedlineGoogle Scholar4. Zeng L, Xiao Q, Chen M, Margariti A, Martin D, Ivetic A, Xu H, Mason J, Wang W, Cockerill G, Mori K, Li JY-S, Chien S, Hu Y, Xu Q. Vascular endothelial growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis.Circulation. 2013; 127:1712–1722.LinkGoogle Scholar5. Silvestre JS, Mallat Z, Tedgui A, Lévy BI. Post-ischaemic neovascularization and inflammation.Cardiovasc Res. 2008; 78:242–249.CrossrefMedlineGoogle Scholar6. Ito WD, Arras M, Winkler B, Scholz D, Schaper J, Schaper W. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion.Circ Res. 1997; 80:829–837.LinkGoogle Scholar7. Heil M, Ziegelhoeffer T, Pipp F, Kostin S, Martin S, Clauss M, Schaper W. Blood monocyte concentration is critical for enhancement of collateral artery growth.Am J Physiol Heart Circ Physiol. 2002; 283:H2411–H2419.CrossrefMedlineGoogle Scholar8. Stabile E, Burnett MS, Watkins C, Kinnaird T, Bachis A, la Sala A, Miller JM, Shou M, Epstein SE, Fuchs S. Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice.Circulation. 2003; 108:205–210.LinkGoogle Scholar9. Stabile E, Kinnaird T, la Sala A, Hanson SK, Watkins C, Campia U, Shou M, Zbinden S, Fuchs S, Kornfeld H, Epstein SE, Burnett MS. CD8+ T lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting CD4+ mononuclear cells through the expression of interleukin-16.Circulation. 2006; 113:118–124.LinkGoogle Scholar10. Cochain C, Rodero MP, Vilar J, Récalde A, Richart AL, Loinard C, Zouggari Y, Guérin C, Duriez M, Combadière B, Poupel L, Lévy BI, Mallat Z, Combadière C, Silvestre JS. Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization.Cardiovasc Res. 2010; 88:186–195.CrossrefMedlineGoogle Scholar11. Zouggari Y, Ait-Oufella H, Waeckel L, Vilar J, Loinard C, Cochain C, Récalde A, Duriez M, Levy BI, Lutgens E, Lutgens E, Mallat Z, Silvestre JS. Regulatory T cells modulate postischemic neovascularization.Circulation. 2009; 120:1415–1425.LinkGoogle Scholar12. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity.Nat Rev Immunol. 2008; 8:663–674.CrossrefMedlineGoogle Scholar13. Loinard C, Zouggari Y, Rueda P, Ramkhelawon B, Cochain C, Vilar J, Récalde A, Richart A, Charue D, Duriez M, Mori M, Arenzana-Seisdedos F, Lévy BI, Heymes C, Silvestre JS. C/EBP homologous protein-10 (CHOP-10) limits postnatal neovascularization through control of endothelial nitric oxide synthase gene expression.Circulation. 2012; 125:1014–1026.LinkGoogle Scholar14. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.Nature. 1999; 399:601–605.CrossrefMedlineGoogle Scholar15. Lehotský J, Urban P, Pavlíková M, Tatarková Z, Kaminska B, Kaplán P. Molecular mechanisms leading to neuroprotection/ischemic tolerance: effect of preconditioning on the stress reaction of endoplasmic reticulum.Cell Mol Neurobiol. 2009; 29:917–925.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Duan Q, Zhou Y and Yang D (2022) Endoplasmic reticulum stress in airway hyperresponsiveness, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2022.112904, 149, (112904), Online publication date: 1-May-2022. Janani R, Anitha R, Perumal M, Divya P and Baskaran V (2021) Astaxanthin mediated regulation of VEGF through HIF1α and XBP1 signaling pathway: An insight from ARPE-19 cell and streptozotocin mediated diabetic rat model, Experimental Eye Research, 10.1016/j.exer.2021.108555, 206, (108555), Online publication date: 1-May-2021. Kalinowski L, Janaszak-Jasiecka A, Siekierzycka A, Bartoszewska S, Woźniak M, Lejnowski D, Collawn J and Bartoszewski R (2016) Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs, Cellular & Molecular Biology Letters, 10.1186/s11658-016-0017-x, 21:1, Online publication date: 1-Dec-2016. Zhao Y, Li Y, Luo P, Gao Y, Yang J, Lao K, Wang G, Cockerill G, Hu Y, Xu Q, Li T and Zeng L (2016) XBP1 splicing triggers miR-150 transfer from smooth muscle cells to endothelial cells via extracellular vesicles, Scientific Reports, 10.1038/srep28627, 6:1, Online publication date: 1-Sep-2016. Zeng L, Li Y, Yang J, Wang G, Margariti A, Xiao Q, Zampetaki A, Yin X, Mayr M, Mori K, Wang W, Hu Y and Xu Q (2015) XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling, Arteriosclerosis, Thrombosis, and Vascular Biology, 35:10, (2134-2144), Online publication date: 1-Oct-2015. Wang N, Zhao F, Lin P, Zhang G, Tang K, Wang A and Jin Y (2017) Knockdown of XBP1 by RNAi in Mouse Granulosa Cells Promotes Apoptosis, Inhibits Cell Cycle, and Decreases Estradiol Synthesis, International Journal of Molecular Sciences, 10.3390/ijms18061152, 18:6, (1152) April 23, 2013Vol 127, Issue 16 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.002336PMID: 23529611 Originally publishedMarch 25, 2013 KeywordsischemiaangiogenesisEditorialstranscription factorsendothelial cellPDF download Advertisement SubjectsAngiogenesis
Referência(s)