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• W2269838541 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 35, No. 8Training Monocytes by Physical Exercise Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTraining Monocytes by Physical ExerciseGood Practice for Improving Collateral Artery Development and Postischemic Outcomes Elisa Avolio, Gaia Spinetti and Paolo Madeddu Elisa AvolioElisa Avolio From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (E.A., P.M.); and MultiMedica Research Institute, Milan, Italy (G.S.). Search for more papers by this author , Gaia SpinettiGaia Spinetti From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (E.A., P.M.); and MultiMedica Research Institute, Milan, Italy (G.S.). Search for more papers by this author and Paolo MadedduPaolo Madeddu From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (E.A., P.M.); and MultiMedica Research Institute, Milan, Italy (G.S.). Search for more papers by this author Originally published1 Aug 2015https://doi.org/10.1161/ATVBAHA.115.306034Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35:1733–1735Peripheral artery disease is caused by obstructing atherosclerotic plaques that critically reduce blood flow during exercise. The disease affects ≈4% of people >40 years and 15% to 20% of subjects above 65 years of age. Critical limb ischemia, the most severe manifestation of peripheral artery disease, describes patients with chronic ischemic rest pain, or patients with ischemic skin lesions, either ulcers or gangrene. It requires foot amputation in 25% of cases within 1 year from the diagnosis. Revascularization therapies are indicated in critical limb ischemia patients, but they are often ineffective or unfeasible; and in the latter case, the reported amputation and mortality rates exceed 50%. Therefore, new therapeutic approaches are urgently needed.See accompanying article on page 1862Promotion of arteriogenesis, which refers to the enlargement and functionalization of preformed collateral arterioles, represents a promising therapeutic approach in critical limb ischemia patients. Several clinical studies have used the administration of growth factors (mostly basic fibroblast growth factor or vascular endothelial growth factor, either as protein or gene therapy) or stem and progenitor cells.1 In addition, exercise rehabilitation programs have been shown to improve symptoms of claudication.2,3 Mechanistic understanding of how physical exercise increases collateral artery formation is inadequate.The new study from Schirmer et al4 shows that voluntary training confers mice with an improved capacity to recover from operatively induced limb ischemia when compared with sedentary controls. The positive outcome is associated with homing of inducible nitric oxide synthase (iNOS)-expressing mononuclear cells. The importance of this cellular mechanism is highlighted by ablative studies in which iNOS was genetically deleted or macrophages and monocytes were pharmacologically depleted. Likewise, bone marrow reconstitution of irradiated mice with iNOS knockout cells inhibits collateral formation and blood flow recovery after ischemia. The authors conclude that iNOS-expressing mononuclear cells might be therapeutically useful for therapeutic collateralization. This could be achieved by stimulation of mononuclear cells release and homing or direct cell transplantation into the ischemic limb.The important role of monocytes in collateral artery formation has been previously established.5 Furthermore, exercise training has been shown to improve regional perfusion in ischemic syndromes by facilitating the release of progenitor cells.6,7 Interestingly, symptomatic tissue ischemia seems to be a prerequisite for induction of proangiogenic cell-mediated reparative mechanisms.7 A novel concept of Schirmer’s study consists of the documentation that iNOS plays a key role in postischemic collateralization. The generation of NO from oxidation of l-arginine (to give citrulline and NO) is catalyzed by 3 distinct members of the NOS family. They are either constitutively expressed in neurons and endothelial cells or induced—as in case of iNOS—by endotoxin or proinflammatory cytokines, such as interleukin-1, tumor necrosis factor-α, and interferon-γ mainly in macrophages. The role of iNOS in cancer angiogenesis is well acknowledged, whereas participation of iNOS in cellular mechanisms of postischemic arteriogenesis represents a novel concept meritoriously introduced by Schirmer et al. However, it remains to be elucidated whether physical training induces the expression of iNOS in monocytes (and if so by which mechanism) or rather promotes the homing of a specific population of iNOS-expressing monocytes.With regard to transcriptional regulation, the sequences of cloned iNOS promoters of all species investigated to date exhibit homologies to binding sites for transcription factors known to be involved in cytokine-mediated induction of transcription. In addition, iNOS promoter coactivators have been recently reported,8 showing the binding of p300 to the iNOS promoter region and demonstrating that p300 overexpression increases interferon-γ–induced iNOS promoter activity. It is therefore possible, yet to be demonstrated, that exercise training exerts a preconditioning action on iNOS transcription through a cytokine-mediated mechanism amplified by ischemia. It would be relevant to investigate if a similar inductive mechanism occurs in proangiogenic progenitor cells previously associated with exercise training7 or instead limited to a specific subpopulation of monocytes/macrophages (Figure). In this respect, we have demonstrated that iNOS expression is induced in cultured circulating proangiogenic progenitor cells by forced expression of human tissue kallikrein (KLK1), a serine protease of the kallikrein–kinin system.9 KLK1 is crucial for cell migration/invasion and is highly abundant not only on proangiogenic CD34 cells but also on CD16 nonclassical monocytes.10 Inhibition of iNOS or scavenging of NO blocks the invasive effect of KLK transduction, supporting the idea that potentiating iNOS can result in better homing of proangiogenic cells. This effect may be dependent on the concomitant presence of the kinin receptor B2R, highly abundant in CD34 progenitor cells,11 and CD16 monocytes.12Download figureDownload PowerPointFigure. Exercise training improves the recovery of the ischemic limb perfusion through a monocytic nitric oxide (NO)-mediated mechanism. BM indicates bone marrow; MNCs, mononuclear cells; and PB, peripheral blood.Exercise programs improve pain free and maximum walking distance in peripheral artery disease patients, but may be impracticable in patients with critical limb ischemia. The direct use of iNOS-expressing monocytes may be considered as a surrogate of physical training in a global therapeutic strategy to alleviate ischemic symptoms. However, caution is necessary when translating promising preclinical studies to the clinical field. For instance, diabetic patients represent a special high cardiovascular risk group in which strategies to ameliorate collateralization of ischemic limbs is particularly desirable. Unfortunately, proangiogenic cells are impaired both at the bone marrow and peripheral blood level with an imbalance in the monocytes subtype proportion toward the M1 proinflammatory counterpart.13,14 Strategies increasing M1 monocytes abundance at the ischemic site could be detrimental in the evolution of peripheral artery disease.In conclusion, iNOS-expressing monocytes seem to play an important role in the collateralization of ischemic limbs of mice. Further studies are necessary to determine their pathogenic role and therapeutic activity in chronic atherosclerotic vascular disease.After a femoral artery ligation, mononuclear cells and progenitor cells are mobilized from the bone marrow and released into the peripheral blood, to be homed into the site of injury. In mice, a regular exercise would favor the increase of a particular class of bone marrow–derived iNOS-overexpressing monocytes, which finally engraft into the ischemic muscle and accumulate around collateral arteries at 7 days post ligation. iNOS-monocytes release NO that, together with the exercise-induced enhancement of shear stress, promotes the growth of collateral arteries (observed as increased number and size of collateral arteries), thus improving the perfusion of the ischemic limb.Sources of FundingThis study was supported by (1) human pericyte progenitor cells and cardiac progenitor cells for specialized stimulation of neovascularization and cardiomyogenesis of the infarcted heart, British Heart Foundation (BHF) Project Grant; (2) manufacture scale up of human pericyte progenitor cells for regenerative medicine, MRC Translational Stem Cell Research Grant.DisclosuresNone.FootnotesCorrespondence to Paolo Madeddu, MD, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin St, Bristol BS2 8HW, United Kingdom. E-mail [email protected]References1. Cooke JP, Losordo DW.Modulating the vascular response to limb ischemia: angiogenic and cell therapies.Circ Res. 2015; 116:1561–1578. doi: 10.1161/CIRCRESAHA.115.303565.LinkGoogle Scholar2. Fokkenrood HJ, Lauret GJ, Verhofstad N, Bendermacher BL, Scheltinga MR, Teijink JA.The effect of supervised exercise therapy on physical activity and ambulatory activities in patients with intermittent claudication.Eur J Vasc Endovasc Surg. 2015; 49:184–191. doi: 10.1016/j.ejvs.2014.11.002.CrossrefMedlineGoogle Scholar3. Lauret GJ, Fakhry F, Fokkenrood HJ, Hunink MG, Teijink JA, Spronk S.Modes of exercise training for intermittent claudication.Cochrane Database Syst Rev. 2014; 7:CD009638. doi: 10.1002/14651858.CD009638.pub2.Google Scholar4. Schirmer SH, Millenaar DN, Werner C, Schuh L, Degen A, Bettink SI, Lipp P, van Rooijen N, Meyer T, Böhm M, Laufs U.Exercise promotes collateral artery growth mediated by monocytic nitric oxide.Arterioscler Thromb Vasc Biol. 2015; 35:1862–1871. doi: 10.1161/ATVBAHA.115.305806.LinkGoogle Scholar5. van Royen N, Piek JJ, Schaper W, Fulton WF.A critical review of clinical arteriogenesis research.J Am Coll Cardiol. 2009; 55:17–25. doi: 10.1016/j.jacc.2009.06.058.CrossrefMedlineGoogle Scholar6. Gielen S, Sandri M, Erbs S, Adams V.Exercise-induced modulation of endothelial nitric oxide production.Curr Pharm Biotechnol. 2011; 12:1375–1384.CrossrefMedlineGoogle Scholar7. Sandri M, Adams V, Gielen S, Linke A, Lenk K, Kränkel N, Lenz D, Erbs S, Scheinert D, Mohr FW, Schuler G, Hambrecht R.Effects of exercise and ischemia on mobilization and functional activation of blood-derived progenitor cells in patients with ischemic syndromes: results of 3 randomized studies.Circulation. 2005; 111:3391–3399. doi: 10.1161/CIRCULATIONAHA.104.527135.LinkGoogle Scholar8. Deng WG, Wu KK.Regulation of inducible nitric oxide synthase expression by p300 and p50 acetylation.J Immunol. 2003; 171:6581–6588.CrossrefMedlineGoogle Scholar9. Spinetti G, Fortunato O, Cordella D, Portararo P, Kränkel N, Katare R, Sala-Newby GB, Richer C, Vincent MP, Alhenc-Gelas F, Tonolo G, Cherchi S, Emanueli C, Madeddu P.Tissue kallikrein is essential for invasive capacity of circulating proangiogenic cells.Circ Res. 2011; 108:284–293. doi: 10.1161/CIRCRESAHA.110.236786.LinkGoogle Scholar10. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ.The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.J Exp Med. 2007; 204:3037–3047. doi: 10.1084/jem.20070885.CrossrefMedlineGoogle Scholar11. Kränkel N, Katare RG, Siragusa M, et al. Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential.Circ Res. 2008; 103:1335–1343. doi: 10.1161/CIRCRESAHA.108.179952.LinkGoogle Scholar12. Kränkel N, Armstrong SP, McArdle CA, Dayan C, Madeddu P.Distinct kinin-induced functions are altered in circulating cells of young type 1 diabetic patients.PLoS One. 2010; 5:e11146. doi: 10.1371/journal.pone.0011146.CrossrefMedlineGoogle Scholar13. Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A.Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus.J Am Coll Cardiol. 2005; 45:1449–1457. doi: 10.1016/j.jacc.2004.11.067.CrossrefMedlineGoogle Scholar14. Fadini GP, de Kreutzenberg SV, Boscaro E, et al. An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy.Diabetologia. 2013; 56:1856–66.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Puca A, Spinetti G, Vono R, Vecchione C and Madeddu P (2016) The genetics of exceptional longevity identifies new druggable targets for vascular protection and repair, Pharmacological Research, 10.1016/j.phrs.2016.10.028, 114, (169-174), Online publication date: 1-Dec-2016. Li P and Luo L (2021) Identification of Critical Genes and Signaling Pathways in Human Monocytes Following High-Intensity Exercise, Healthcare, 10.3390/healthcare9060618, 9:6, (618) August 2015Vol 35, Issue 8 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.115.306034PMID: 26203159 Originally publishedAugust 1, 2015 PDF download Advertisement" @default.
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