EDITORIAL
Cardiovascular Research (2015) 107, 200–202 doi:10.1093/cvr/cvv174
Stimulating arteriogenesis but not atherosclerosis: IFN-a/b receptor subunit 1 as a novel therapeutic target Cle´ment Cochain and Alma Zernecke* Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Wu¨rzburg, Josef-Schneider-Str. 2, Wu¨rzburg 97080, Germany Online publish-ahead-of-print 17 June 2015
This editorial refers to ‘MAb therapy against the IFN-a/b receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden’ by P.F.A. Teunissen et al., pp. 255 –266.
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
* Corresponding author. Tel: +49 931 31 83171; fax: +49 931 32 93630, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from by guest on March 22, 2016
In ischaemic diseases such as myocardial infarction (MI), restoration of sufficient blood supply to ischaemic areas through arteriogenesis is critical for preservation of tissue integrity and function.1 Although ischaemia activates natural mechanisms promoting arteriogenesis, these are often insufficient to alleviate the consequences of ischaemia in patients, prompting the need for novel therapeutic strategies.1 One significant hurdle, however, is that several pro-arteriogenic mechanisms and therapeutic approaches also promote atherosclerotic plaque development.1,2 Teunissen et al. 3 now show that targeting the IFN-a/b receptor subunit 1 (IFNAR1) stimulates functional perfusion of ischaemic tissue while only minimally affecting atherosclerosis. Arteriogenic and atherosclerotic processes often engage similar mechanisms. For example, limb ischaemia induces the mobilization of Ly6Chigh monocytes to the bloodstream, which then infiltrate ischaemic tissue to promote blood flow recovery in mice,4 but also constitutes the main precursors of atherosclerotic plaque macrophages. 5 Myocardial or peripheral ischaemia furthermore activates the sympathetic nervous system to trigger the release of progenitor cells from the bone marrow,6,7 which, in turn, stimulate neovascularization. 7 This, however, also promotes vascular inflammation and leads to an acceleration of atherosclerosis after MI. 6 Conversely, some antiatherogenic cytokines, for example IL-10,8 inhibit arteriogenesis. The pro-arteriogenic and pro-atherosclerotic nature of many pathways has also complicated the development of therapeutic strategies,2 and different pro-arteriogenic strategies such as administration of CCL29 or infusion of bone marrow-derived mononuclear cells10 promoted neovascularization, but simultaneously increased atherosclerosis in hypercholesterolaemic mice in pre-clinical studies (Figure 1). Previous work had suggested that type I IFN (IFN-a and IFN-b) signalling may constitute a potential therapeutic target, as it interfered with arteriogenesis but promoted atherosclerosis. For instance, an
increased IFN-b signalling was found in MI patients with poor collateral vessel networks,11 and IFN-b administration reduced post-ischaemic perfusion recovery.11 In contrast, IFN-b aggravated atherosclerosis in mice,12 and IFNAR1 deficiency in myeloid cells attenuated lesion formation.12 Teunissen et al. have now evaluated the effects of blocking IFNAR1 on arteriogenesis and atherosclerosis in hypercholesterolaemic mice. In low-density lipoprotein receptor-deficient (Ldlr 2/ 2 ) mice fed a Western diet, administration of an anti-IFNAR1 mAb for 4 weeks improved blood flow recovery in ischaemic paws, but left atherosclerotic plaque size unaltered. Plaque analyses showed a mostly similar composition between groups, except for a higher proportion of macrophages and a reduction in plaque cell apoptosis in lesions of anti-IFNAR1-treated mice. In another model, apolipoprotein E-deficient mice with established plaques were treated with antiIFNAR1 for 1 week, which again resulted in an increased perfusion after ischaemia, and was accompanied by an increased arteriolar lumen size, as well as decreased expression of CXCL-10, a downstream target of IFNAR1 signalling, which had previously been proposed to either activate13 or inhibit14 tissue neovascularization. In this short-term model, IFNAR1 blockade had no effects on atherosclerotic lesions. Investigating effects on hindlimb ischaemia in atherosclerorosisprone mice as a model of patients affected by both ischaemia and atherosclerosis, this study thus provides encouraging evidence that blocking type I IFN signalling may be a relevant therapeutic strategy for ischaemic diseases in patients. However, a number of questions remain. The mechanisms underlying improved perfusion recovery upon anti-IFNAR1 treatment are still unclear. In particular, it remains to be determined, which cell type(s) is/are responsible for the effects of IFNAR1 blockade on neovascularization. Upon short-term treatment, macrophage infiltration, M1/M2 macrophage polarization, and expression of arteriogenic cytokines were not altered. Discrete local changes in macrophage phenotype and cytokine expression, however, may have gone unnoticed in these analyses. Effects of IFNAR1 blockade may also depend on smooth muscle cells, as previously proposed.15 AntiIFNAR1 treatment resulted in only small changes in vessel density and size in ischaemic tissues, except for an increased arteriolar lumen size upon short-term treatment; alternative mechanisms, such as an
201
Editorial
kines (e.g. IL-10) inhibit arteriogenesis, whereas some pro-arteriogenic strategies (bone marrow mononuclear cell infusion and CCL2 administration) promote atherosclerotic plaque growth. IFN-b was shown to inhibit arteriogenesis and to promote atherosclerosis. Teunissen et al. have now provided evidence that a mAb-based therapeutic strategy blocking IFNAR1, the receptor of IFN-b and IFN-a, promotes arteriogenesis and blood perfusion recovery after hindlimb ischaemia, while having no effects on atherosclerotic plaque growth.
improved endothelial-dependent vasorelaxation following IFNAR1 blockade16 could thus also be underlying ameliorated perfusion recovery. Deciphering the cell type-specific effects of IFNAR1 signalling in arteriogenesis and atherosclerosis, for example by using mice with a conditional deficiency of IFNAR1, as well as dissecting potential effects of the IFNAR1 ligands IFN-a and IFN-b would clearly be of interest. One other important aspect that deserves attention in future studies is the increased macrophage content of atherosclerotic plaques of Ldlr 2/2 mice. Although this was observed in experiments of early lesion development after 4 weeks of diet, effects of longer-term antiIFNAR1 treatment in mice with established plaques await to be evaluated. Given the increased IFN-b signalling in patients with MI,11 it will also be important to study whether anti-IFNAR1 treatment functions to ameliorate neovascularization after MI, and to analyse whether it has an impact on MI-triggered acceleration of atherosclerosis.6 In conclusion, findings by Teunissen et al. open up new possibilities to tackle what was once coined the ‘Janus phenomenon’,2 indicating that pro-arteriogenic therapeutic strategies tend to promote atherosclerotic lesion growth. Targeting type I IFN signalling appears as a promising therapeutic strategy for promoting arteriogenesis without affecting atherosclerosis, and calls for further research in this area.
References 1. Silvestre JS, Smadja DM, Levy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013;93:1743 –1802. 2. Epstein SE, Stabile E, Kinnaird T, Lee CW, Clavijo L, Burnett MS. Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance collateral formation and those designed to inhibit atherogenesis. Circulation 2004;109:2826 –2831. 3. Teunissen PF, Boshuizen MC, Hollander MR, Biesbroek PS, van der Hoeven NW, Mol JQ, Gijbels MJ, van der Velden S, van der Pouw Kraan TC, Horrevoets AJ, de Winther MP, van Royen N. Monoclonal antibody therapy against the interferon-alpha/beta receptor subunit 1 stimulates arteriogenesis in a murine hindlimb-ischemia model without enhancing atherosclerotic burden. Cardiovasc Res 2015;107:255 –266. 4. Cochain C, Rodero MP, Vilar J, Recalde A, Richart AL, Loinard C, Zouggari Y, Guerin C, Duriez M, Combadiere B, Poupel L, Levy BI, Mallat Z, Combadiere C, Silvestre JS. Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization. Cardiovasc Res 2010;88:186–195. 5. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007;117:195–205. 6. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature 2012;487: 325 –329.
Downloaded from by guest on March 22, 2016
Figure 1 After arterial occlusion, arteriogenesis promotes blood perfusion recovery, hence alleviating tissue ischaemia. Some anti-atherogenic cyto-
202 7. Recalde A, Richart A, Guerin C, Cochain C, Zouggari Y, Yin KH, Vilar J, Drouet I, Levy B, Varoquaux O, Silvestre JS. Sympathetic nervous system regulates bone marrow-derived cell egress through endothelial nitric oxide synthase activation: role in postischemic tissue remodeling. Arterioscler Thromb Vasc Biol 2012;32: 643 – 653. 8. Silvestre JS, Mallat Z, Duriez M, Tamarat R, Bureau MF, Scherman D, Duverger N, Branellec D, Tedgui A, Levy BI. Antiangiogenic effect of interleukin-10 in ischemiainduced angiogenesis in mice hindlimb. Circ Res 2000;87:448–452. 9. van Royen N, Hoefer I, Bottinger M, Hua J, Grundmann S, Voskuil M, Bode C, Schaper W, Buschmann I, Piek JJ. Local monocyte chemoattractant protein-1 therapy increases collateral artery formation in apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression, neointimal formation, and plaque progression. Circ Res 2003;92:218 –225. 10. Silvestre JS, Gojova A, Brun V, Potteaux S, Esposito B, Duriez M, Clergue M, Le Ricousse-Roussanne S, Barateau V, Merval R, Groux H, Tobelem G, Levy B, Tedgui A, Mallat Z. Transplantation of bone marrow-derived mononuclear cells in ischemic apolipoprotein E-knockout mice accelerates atherosclerosis without altering plaque composition. Circulation 2003;108:2839 –2842. 11. Schirmer SH, Fledderus JO, Bot PT, Moerland PD, Hoefer IE, Baan J Jr, Henriques JP, van der Schaaf RJ, Vis MM, Horrevoets AJ, Piek JJ, van Royen N. Interferon-beta signaling
Editorial
12.
13.
14. 15.
16.
is enhanced in patients with insufficient coronary collateral artery development and inhibits arteriogenesis in mice. Circ Res 2008;102:1286 –1294. Goossens P, Gijbels MJ, Zernecke A, Eijgelaar W, Vergouwe MN, van der Made I, Vanderlocht J, Beckers L, Buurman WA, Daemen MJ, Kalinke U, Weber C, Lutgens E, de Winther MP. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab 2010;12:142 –153. van den Borne P, Haverslag RT, Brandt MM, Cheng C, Duckers HJ, Quax PH, Hoefer IE, Pasterkamp G, de Kleijn DP. Absence of chemokine (C-X-C motif) ligand 10 diminishes perfusion recovery after local arterial occlusion in mice. Arterioscler Thromb Vasc Biol 2014;34:594 –602. Bodnar RJ, Yates CC, Rodgers ME, Du X, Wells A. Ip-10 induces dissociation of newly formed blood vessels. J Cell Sci 2009;122:2064 –2077. Schirmer SH, Bot PT, Fledderus JO, van der Laan AM, Volger OL, Laufs U, Bohm M, de Vries CJ, Horrevoets AJ, Piek JJ, Hoefer IE, van Royen N. Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis. J Biol Chem 2010;285:34677 –34685. Thacker SG, Zhao W, Smith CK, Luo W, Wang H, Vivekanandan-Giri A, Rabquer BJ, Koch AE, Pennathur S, Davidson A, Eitzman DT, Kaplan MJ. Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum 2012;64:2975 –2985.
Downloaded from by guest on March 22, 2016
Cardiovascular Research (2015) 107, 200–202 doi:10.1093/cvr/cvv174
Stimulating arteriogenesis but not atherosclerosis: IFN-a/b receptor subunit 1 as a novel therapeutic target Cle´ment Cochain and Alma Zernecke* Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Wu¨rzburg, Josef-Schneider-Str. 2, Wu¨rzburg 97080, Germany Online publish-ahead-of-print 17 June 2015
This editorial refers to ‘MAb therapy against the IFN-a/b receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden’ by P.F.A. Teunissen et al., pp. 255 –266.
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
* Corresponding author. Tel: +49 931 31 83171; fax: +49 931 32 93630, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from by guest on March 22, 2016
In ischaemic diseases such as myocardial infarction (MI), restoration of sufficient blood supply to ischaemic areas through arteriogenesis is critical for preservation of tissue integrity and function.1 Although ischaemia activates natural mechanisms promoting arteriogenesis, these are often insufficient to alleviate the consequences of ischaemia in patients, prompting the need for novel therapeutic strategies.1 One significant hurdle, however, is that several pro-arteriogenic mechanisms and therapeutic approaches also promote atherosclerotic plaque development.1,2 Teunissen et al. 3 now show that targeting the IFN-a/b receptor subunit 1 (IFNAR1) stimulates functional perfusion of ischaemic tissue while only minimally affecting atherosclerosis. Arteriogenic and atherosclerotic processes often engage similar mechanisms. For example, limb ischaemia induces the mobilization of Ly6Chigh monocytes to the bloodstream, which then infiltrate ischaemic tissue to promote blood flow recovery in mice,4 but also constitutes the main precursors of atherosclerotic plaque macrophages. 5 Myocardial or peripheral ischaemia furthermore activates the sympathetic nervous system to trigger the release of progenitor cells from the bone marrow,6,7 which, in turn, stimulate neovascularization. 7 This, however, also promotes vascular inflammation and leads to an acceleration of atherosclerosis after MI. 6 Conversely, some antiatherogenic cytokines, for example IL-10,8 inhibit arteriogenesis. The pro-arteriogenic and pro-atherosclerotic nature of many pathways has also complicated the development of therapeutic strategies,2 and different pro-arteriogenic strategies such as administration of CCL29 or infusion of bone marrow-derived mononuclear cells10 promoted neovascularization, but simultaneously increased atherosclerosis in hypercholesterolaemic mice in pre-clinical studies (Figure 1). Previous work had suggested that type I IFN (IFN-a and IFN-b) signalling may constitute a potential therapeutic target, as it interfered with arteriogenesis but promoted atherosclerosis. For instance, an
increased IFN-b signalling was found in MI patients with poor collateral vessel networks,11 and IFN-b administration reduced post-ischaemic perfusion recovery.11 In contrast, IFN-b aggravated atherosclerosis in mice,12 and IFNAR1 deficiency in myeloid cells attenuated lesion formation.12 Teunissen et al. have now evaluated the effects of blocking IFNAR1 on arteriogenesis and atherosclerosis in hypercholesterolaemic mice. In low-density lipoprotein receptor-deficient (Ldlr 2/ 2 ) mice fed a Western diet, administration of an anti-IFNAR1 mAb for 4 weeks improved blood flow recovery in ischaemic paws, but left atherosclerotic plaque size unaltered. Plaque analyses showed a mostly similar composition between groups, except for a higher proportion of macrophages and a reduction in plaque cell apoptosis in lesions of anti-IFNAR1-treated mice. In another model, apolipoprotein E-deficient mice with established plaques were treated with antiIFNAR1 for 1 week, which again resulted in an increased perfusion after ischaemia, and was accompanied by an increased arteriolar lumen size, as well as decreased expression of CXCL-10, a downstream target of IFNAR1 signalling, which had previously been proposed to either activate13 or inhibit14 tissue neovascularization. In this short-term model, IFNAR1 blockade had no effects on atherosclerotic lesions. Investigating effects on hindlimb ischaemia in atherosclerorosisprone mice as a model of patients affected by both ischaemia and atherosclerosis, this study thus provides encouraging evidence that blocking type I IFN signalling may be a relevant therapeutic strategy for ischaemic diseases in patients. However, a number of questions remain. The mechanisms underlying improved perfusion recovery upon anti-IFNAR1 treatment are still unclear. In particular, it remains to be determined, which cell type(s) is/are responsible for the effects of IFNAR1 blockade on neovascularization. Upon short-term treatment, macrophage infiltration, M1/M2 macrophage polarization, and expression of arteriogenic cytokines were not altered. Discrete local changes in macrophage phenotype and cytokine expression, however, may have gone unnoticed in these analyses. Effects of IFNAR1 blockade may also depend on smooth muscle cells, as previously proposed.15 AntiIFNAR1 treatment resulted in only small changes in vessel density and size in ischaemic tissues, except for an increased arteriolar lumen size upon short-term treatment; alternative mechanisms, such as an
201
Editorial
kines (e.g. IL-10) inhibit arteriogenesis, whereas some pro-arteriogenic strategies (bone marrow mononuclear cell infusion and CCL2 administration) promote atherosclerotic plaque growth. IFN-b was shown to inhibit arteriogenesis and to promote atherosclerosis. Teunissen et al. have now provided evidence that a mAb-based therapeutic strategy blocking IFNAR1, the receptor of IFN-b and IFN-a, promotes arteriogenesis and blood perfusion recovery after hindlimb ischaemia, while having no effects on atherosclerotic plaque growth.
improved endothelial-dependent vasorelaxation following IFNAR1 blockade16 could thus also be underlying ameliorated perfusion recovery. Deciphering the cell type-specific effects of IFNAR1 signalling in arteriogenesis and atherosclerosis, for example by using mice with a conditional deficiency of IFNAR1, as well as dissecting potential effects of the IFNAR1 ligands IFN-a and IFN-b would clearly be of interest. One other important aspect that deserves attention in future studies is the increased macrophage content of atherosclerotic plaques of Ldlr 2/2 mice. Although this was observed in experiments of early lesion development after 4 weeks of diet, effects of longer-term antiIFNAR1 treatment in mice with established plaques await to be evaluated. Given the increased IFN-b signalling in patients with MI,11 it will also be important to study whether anti-IFNAR1 treatment functions to ameliorate neovascularization after MI, and to analyse whether it has an impact on MI-triggered acceleration of atherosclerosis.6 In conclusion, findings by Teunissen et al. open up new possibilities to tackle what was once coined the ‘Janus phenomenon’,2 indicating that pro-arteriogenic therapeutic strategies tend to promote atherosclerotic lesion growth. Targeting type I IFN signalling appears as a promising therapeutic strategy for promoting arteriogenesis without affecting atherosclerosis, and calls for further research in this area.
References 1. Silvestre JS, Smadja DM, Levy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013;93:1743 –1802. 2. Epstein SE, Stabile E, Kinnaird T, Lee CW, Clavijo L, Burnett MS. Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance collateral formation and those designed to inhibit atherogenesis. Circulation 2004;109:2826 –2831. 3. Teunissen PF, Boshuizen MC, Hollander MR, Biesbroek PS, van der Hoeven NW, Mol JQ, Gijbels MJ, van der Velden S, van der Pouw Kraan TC, Horrevoets AJ, de Winther MP, van Royen N. Monoclonal antibody therapy against the interferon-alpha/beta receptor subunit 1 stimulates arteriogenesis in a murine hindlimb-ischemia model without enhancing atherosclerotic burden. Cardiovasc Res 2015;107:255 –266. 4. Cochain C, Rodero MP, Vilar J, Recalde A, Richart AL, Loinard C, Zouggari Y, Guerin C, Duriez M, Combadiere B, Poupel L, Levy BI, Mallat Z, Combadiere C, Silvestre JS. Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization. Cardiovasc Res 2010;88:186–195. 5. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007;117:195–205. 6. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature 2012;487: 325 –329.
Downloaded from by guest on March 22, 2016
Figure 1 After arterial occlusion, arteriogenesis promotes blood perfusion recovery, hence alleviating tissue ischaemia. Some anti-atherogenic cyto-
202 7. Recalde A, Richart A, Guerin C, Cochain C, Zouggari Y, Yin KH, Vilar J, Drouet I, Levy B, Varoquaux O, Silvestre JS. Sympathetic nervous system regulates bone marrow-derived cell egress through endothelial nitric oxide synthase activation: role in postischemic tissue remodeling. Arterioscler Thromb Vasc Biol 2012;32: 643 – 653. 8. Silvestre JS, Mallat Z, Duriez M, Tamarat R, Bureau MF, Scherman D, Duverger N, Branellec D, Tedgui A, Levy BI. Antiangiogenic effect of interleukin-10 in ischemiainduced angiogenesis in mice hindlimb. Circ Res 2000;87:448–452. 9. van Royen N, Hoefer I, Bottinger M, Hua J, Grundmann S, Voskuil M, Bode C, Schaper W, Buschmann I, Piek JJ. Local monocyte chemoattractant protein-1 therapy increases collateral artery formation in apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression, neointimal formation, and plaque progression. Circ Res 2003;92:218 –225. 10. Silvestre JS, Gojova A, Brun V, Potteaux S, Esposito B, Duriez M, Clergue M, Le Ricousse-Roussanne S, Barateau V, Merval R, Groux H, Tobelem G, Levy B, Tedgui A, Mallat Z. Transplantation of bone marrow-derived mononuclear cells in ischemic apolipoprotein E-knockout mice accelerates atherosclerosis without altering plaque composition. Circulation 2003;108:2839 –2842. 11. Schirmer SH, Fledderus JO, Bot PT, Moerland PD, Hoefer IE, Baan J Jr, Henriques JP, van der Schaaf RJ, Vis MM, Horrevoets AJ, Piek JJ, van Royen N. Interferon-beta signaling
Editorial
12.
13.
14. 15.
16.
is enhanced in patients with insufficient coronary collateral artery development and inhibits arteriogenesis in mice. Circ Res 2008;102:1286 –1294. Goossens P, Gijbels MJ, Zernecke A, Eijgelaar W, Vergouwe MN, van der Made I, Vanderlocht J, Beckers L, Buurman WA, Daemen MJ, Kalinke U, Weber C, Lutgens E, de Winther MP. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab 2010;12:142 –153. van den Borne P, Haverslag RT, Brandt MM, Cheng C, Duckers HJ, Quax PH, Hoefer IE, Pasterkamp G, de Kleijn DP. Absence of chemokine (C-X-C motif) ligand 10 diminishes perfusion recovery after local arterial occlusion in mice. Arterioscler Thromb Vasc Biol 2014;34:594 –602. Bodnar RJ, Yates CC, Rodgers ME, Du X, Wells A. Ip-10 induces dissociation of newly formed blood vessels. J Cell Sci 2009;122:2064 –2077. Schirmer SH, Bot PT, Fledderus JO, van der Laan AM, Volger OL, Laufs U, Bohm M, de Vries CJ, Horrevoets AJ, Piek JJ, Hoefer IE, van Royen N. Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis. J Biol Chem 2010;285:34677 –34685. Thacker SG, Zhao W, Smith CK, Luo W, Wang H, Vivekanandan-Giri A, Rabquer BJ, Koch AE, Pennathur S, Davidson A, Eitzman DT, Kaplan MJ. Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum 2012;64:2975 –2985.
Downloaded from by guest on March 22, 2016
