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Progenitor Cells, Bone Marrow–Derived Fibrocytes and Endothelial-to-Mesenchymal Transition

2015; Lippincott Williams & Wilkins; Volume: 67; Issue: 2 Linguagem: Inglês

10.1161/hypertensionaha.115.06220

1524-4563

Francisco J. Rios, Adam Harvey, Rhéure Alves-Lopes, Augusto C. Montezano, Rhian M. Touyz,

Systemic Sclerosis and Related Diseases

HomeHypertensionVol. 67, No. 2Progenitor Cells, Bone Marrow–Derived Fibrocytes and Endothelial-to-Mesenchymal Transition Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBProgenitor Cells, Bone Marrow–Derived Fibrocytes and Endothelial-to-Mesenchymal TransitionNew Players in Vascular Fibrosis Francisco J. Rios, Adam Harvey, Rheure A. Lopes, Augusto C. Montezano and Rhian M. Touyz Francisco J. RiosFrancisco J. Rios From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. , Adam HarveyAdam Harvey From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. , Rheure A. LopesRheure A. Lopes From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. , Augusto C. MontezanoAugusto C. Montezano From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. and Rhian M. TouyzRhian M. Touyz From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. Originally published22 Dec 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.06220Hypertension. 2016;67:272–274Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 See related article, pp 461–468Tissue fibrosis, defined as an excessive accumulation of extracellular matrix (ECM) components leading to the destruction of organ architecture and impaired function, affects virtually every tissue and organ in the body, including the arteries. Vascular fibrosis of small and large arteries contributes to arterial remodeling, important in the development and complications of hypertension.1 Fibrogenesis is an active process that involves accumulation of structural proteins (collagen and fibronectin) and adhesion proteins (laminin and fibronectin), expression of adhesion molecules and integrins, and remodeling of the ECM.2 Healthy arteries are surrounded by perivascular adventitial tissue comprising collagens I and III in the intima, media, and adventitia, with collagen types I, III, IV, and V in the endothelial and vascular smooth muscle cell basement membranes.3 These fibrillar proteins maintain vascular integrity and normal vascular tone and function. In hypertension, accumulation of collagen and fibronectin and ECM reorganization lead to increased stiffness of the vessel wall.4 Initially, these processes are adaptive and reversible and may compensate for higher blood pressures, but with time and progressive increases in blood pressure, this becomes maladaptive and decompensated, leading to arterial stiffness that contributes to hypertension-associated target organ damage. These events have been demonstrated in many experimental models of hypertension and in hypertensive patients and have been attributed to activation of ERK1/2, p38mitogen-activated protein kinase, transforming growth factor-β, SMAD pathways, oxidative stress, and dysregulation of matrix metalloproteinases.2 Decreased activation of matrix metalloproteinases and increased activity of tissue inhibitors of metalloproteinase leads to reduced collagen turnover and consequent accumulation, with thickening and remodeling of the vascular wall.Vascular fibrosis is a dynamic and active phenomenon, where a proinflammatory, oxidative milieu, triggered by prohypertensive stimuli, lays the foundation for fibrosis and activation of ECM-producing cells. Until recently the process seemed fairly simple where adventitial fibroblasts and myofibroblasts were considered the major collagen-producing cells in the vascular wall.2 What is becoming increasingly evident is that a whole array of cells have potential to produce ECM proteins. In fact, myofibroblasts are differentiated from various precursors including adventitial fibroblasts, pericytes, phenotypic transition of endothelial cells, phenotypic modulation of vascular smooth muscle cells, and recruitment of circulating multipotent monocytes and fibrocytes.5 However, the scenario continues to become more complex, Wu et al5 demonstrated that 3 previously unidentified cell types, including stem cell antigen-1 (Sca-1)+ progenitor cells, bone marrow–derived infiltrating fibrobrocytes, and cells of endothelial origin (endothelial-to-mesenchymal transition [EMT]) are major vascular-fibrosing cells in hypertension. These findings underscore the complexity of fibrogenesis and highlight the heterogeneous cell pool that contributes to ECM production, vascular fibrosis, and arterial stiffening.Moreover, and rather intriguingly, it seems that predifferentiated resident fibroblasts represent only a minor fraction of ECM-producing cells in hypertension, with Sca-1+ cells and bone marrow–derived cells accounting for >50% of aortic collagen-producing cells and cells of endothelial origin contributing ≈25%.5 These findings further indicate that not only are there multiple types of ECM proteins (elastin, fibrin, and fibronectin) and collagens (I, III, and IV) contribute to fibrosis but the process is highly regulated and involves transformation, recruitment, and activation of different types of collagen-producing cells.Sca-1 is an 18-kDa mouse glycosyl phosphatidylinositol-anchored cell surface protein of the Ly6 gene family.6 It was originally identified as an antigen that was upregulated on activated lymphocytes, and it is commonly used as a marker of hematopoietic stem cells. Beyond the hematopoietic system, Sca-1 is expressed in a mixture of stem, progenitor, and differentiated cell types, in various tissues and organs, including the heart and vessels.6 Sca-1+ adventitial cells are embryonic hematopoietic cells and have the capacity to differentiate into various vascular cell types, including vascular smooth muscle cells.7 In the heart, resident Sca-1+ cells may play a regenerative role post myocardial infarction and in the vascular wall,7 resident Sca-1+ cells have been implicated in remodeling associated with arteriosclerosis. Resident vascular adventitial macrophage Sca-1+ progenitor cells are abundant in atherosclerotic lesions in hyperlipidemic apolipoprotein E(–/–) and low-density lipoprotein receptor (–/–) mice.8 Taken together, these data suggest that Sca-1+ cells play a role in atherogenesis. Extending these findings, Wu et al5 show that resident vascular Sca-1+ cells also contribute to vascular fibrosis in angiotensin II–induced hypertension. Factors that trigger such events have not been clearly elucidated, but the fact that Sca-1+ cells were found to be a major source of collagen in aortic fibrosis in hypertension indicates that highly regulated systems must be involved. Although these intriguing findings highlight a key role for embryonic Sca-1+ hematopoietic-derived cells in vascular fibrosis in a mouse model of hypertension, the clinical relevance remains unclear because Sca-1+ antigen is absent in humans.6Not only resident Sca-1+ progenitor cells were identified to be a significant source of collagen in vascular fibrosis5 but bone marrow–derived circulating fibrocytes were found to be especially important and to constitute the majority of cell types responsible for ECM production in the aorta in angiotensin II–induced hypertension. This is not a new finding because others have demonstrated that bone marrow–derived circulating progenitor cells are recruited to sites of vascular injury and to assume endothelial, smooth muscle-like and fibroblast-like phenotypes.9 Fibrocytes that express leukocyte antigen CD45, produce ECM components and ECM-modifying enzymes, such as matrix metalloproteinases, and can differentiate into myofibroblasts and play a role in vascular remodeling and fibrosis in pulmonary hypertension. In angiotensin II–induced hypertension, fibrocytes seem to be especially important in vascular fibrosis because Wu et al5 found that the majority of collagen I–producing cells of the aorta are CD45+Col I+ bone marrow–derived fibrocytes.5 What still needs to be identified are the specific factors involved in the recruitment and retention of these cells, although an underlying proinflammatory environment could be important because chemokines and cytokines seem to attract circulating fibrocytes to the vascular wall.5Wu et al5 described a third novel mechanism contributing to aortic fibrosis in angiotensin II–induced hypertension, involving EMT, a process whereby differentiated endothelial cells undergo a phenotypic conversion to matrix-producing fibroblasts and myofibroblasts. EMT is usually preceded by and closely associated with inflammation and may be an adaptive response to endothelial injury.10 Underlying vascular inflammation in hypertension may stimulate signaling pathways such as transforming growth factor-β/SMAD, integrin-linked kinase, and Wnt/b-catenin, which are critically involved in the process of EMT.10 Interestingly, many of these signaling molecules are themselves implicated in the production of ECM proteins. Hence, molecular mechanisms promoting EMT are similar to those that drive fibrosis, and as such may be putative targets of antifibrotic therapy.Although a new paradigm in aortic fibrosis in hypertension has been defined,5 there are a number of questions that still need to be answered. First, do similar cellular populations participate in vascular fibrosis of small arteries, the vessels that contribute to increased resistance and blood pressure elevation? Second, do Sca-1+ cells, bone marrow–derived fibrocytes and EMT cells in the vascular wall produce different types of ECM proteins and collagens? Third, do the cell types have a distinct localization in the aorta and are they activated at different time points during fibrogenesis? Fourth, what triggers the activation of these apparently unrelated cells to become profibrogenic and finally, what are the signaling pathways and mechanisms that regulate these different cell types to produce collagen and other ECM in a regulated and organized manner in the vascular wall?Our previous notion that adventitial resident fibroblasts are the cellular origin and backbone of vascular fibrosis clearly needs to change, and based on the findings of Wu et al,5 we need to now think of fibrosis as a complex multicellular phenomenon where recruitment, differentiation, and transformation of various cell types define the ECM in hypertension. Moreover, from a therapeutic viewpoint, this new paradigm highlights the potential importance to target multiple cell types and different systems in the prevention of vascular fibrosis and aortic stiffening in hypertension (Figure).Download figureDownload PowerPointFigure. Diagram demonstrating a role for multiple cell types in vascular fibrosis in hypertension. Prohypertensive factors, such as angiotensin II (Ang II) and proinflammatory stimuli, stimulate activation of bone marrow–derived fibrocytes, Sca-1+ vascular cells, resident fibroblasts, and myofibroblasts as well as endothelial-to-mesenchymal transition (EMT). Inflammation in particular stimulates EMT. Activation of these cells is associated with stimulation of profibrotic-signaling pathways, leading to production of extracellular matrix (ECM) proteins, such as collagens and fibronectin. These processes lead to vascular fibrosis and arterial stiffening in hypertension. The study by Wu et al5 suggests that the major cell types contributing to vascular fibrosis in Ang II–induced hypertension involve bone marrow–derived fibrocytes and Sca-1+ cells. ILK indicates integrin-linked kinase; MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species; and TGF-β, transforming growth factor-β.Sources of FundingThis work from the author's laboratory was supported by grants from the British Heart Foundation (BHF) (RG/13/7/30099). R.M. Touyz is supported through a BHF Chair (CH/12/4/29762).DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.This paper was sent to R. Clinton Webb, Guest Editor, for review by expert referees, editorial decision, and final disposition.Correspondence to Rhian M. Touyz, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. E-mail: [email protected]References1. Savoia C, Burger D, Nishigaki N, Montezano A, Touyz RM. Angiotensin II and the vascular phenotype in hypertension.Expert Rev Mol Med. 2011; 13:e11. doi: 10.1017/S1462399411001815.CrossrefMedlineGoogle Scholar2. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease.Nat Med. 2012; 18:1028–1040. doi: 10.1038/nm.2807.CrossrefMedlineGoogle Scholar3. Osidak MS, Osidak EO, Akhmanova MA, Domogatsky SP, Domogatskaya AS. Fibrillar, fibril-associated and basement membrane collagens of the arterial wall: architecture, elasticity and remodeling under stress.Curr Pharm Des. 2015; 21:1124–1133.CrossrefMedlineGoogle Scholar4. Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing-Implications in hypertension.J Mol Cell Cardiol. 2015; 83:112–121. doi: 10.1016/j.yjmcc.2015.04.011.CrossrefMedlineGoogle Scholar5. Wu J, Montaniel KRC, Saleh MA, Xiao L, Chen W, Owens GK, Humphrey JD, Majesky MW, Paik DT, Hatzopoulos AK, Madhur MS, Harrison DG. Origin of matrix-producing cells that contribute to aortic fibrosis in hypertension.Hypertension. 2016; 67:461–468. doi: 10.1161/HYPERTENSIONAHA.115.06123.LinkGoogle Scholar6. Holmes C, Stanford WL. Concise review: stem cell antigen-1: expression, function, and enigma.Stem Cells. 2007; 25:1339–1347. doi: 10.1634/stemcells.2006-0644.CrossrefMedlineGoogle Scholar7. Psaltis PJ, Puranik AS, Spoon DB, Chue CD, Hoffman SJ, Witt TA, Delacroix S, Kleppe LS, Mueske CS, Pan S, Gulati R, Simari RD. Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature.Circ Res. 2014; 115:364–375. doi: 10.1161/CIRCRESAHA.115.303299.LinkGoogle Scholar8. Tolani S, Pagler TA, Murphy AJ, Bochem AE, Abramowicz S, Welch C, Nagareddy PR, Holleran S, Hovingh GK, Kuivenhoven JA, Tall AR. Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children.Atherosclerosis. 2013; 229:79–85. doi: 10.1016/j.atherosclerosis.2013.03.031.CrossrefMedlineGoogle Scholar9. Li J, Tan H, Wang X, Li Y, Samuelson L, Li X, Cui C, Gerber DA. Circulating fibrocytes stabilize blood vessels during angiogenesis in a paracrine manner.Am J Pathol. 2014; 184:556–571. doi: 10.1016/j.ajpath.2013.10.021.CrossrefMedlineGoogle Scholar10. Medici D, Kalluri R. Endothelial-mesenchymal transition and its contribution to the emergence of stem cell phenotype.Semin Cancer Biol. 2012; 22:379–384. doi: 10.1016/j.semcancer.2012.04.004.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hou Z, Yan W, Li T, Wu W, Cui Y, Zhang X, Chen Y, Yin T, Qiu J and Wang G (2020) Lactic acid-mediated endothelial to mesenchymal transition through TGF-β1 contributes to in-stent stenosis in poly-L-lactic acid stent, International Journal of Biological Macromolecules, 10.1016/j.ijbiomac.2019.11.136, 155, (1589-1598), Online publication date: 1-Jul-2020. Martinez-Quinones P, McCarthy C, Watts S, Klee N, Komic A, Calmasini F, Priviero F, Warner A, Chenghao Y and Wenceslau C (2018) Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall, American Journal of Hypertension, 10.1093/ajh/hpy083, 31:10, (1067-1078), Online publication date: 11-Sep-2018. Awgulewitsch C, Trinh L and Hatzopoulos A (2017) The Vascular Wall: a Plastic Hub of Activity in Cardiovascular Homeostasis and Disease, Current Cardiology Reports, 10.1007/s11886-017-0861-y, 19:6, Online publication date: 1-Jun-2017. Verdura E, Hervé D, Bergametti F, Jacquet C, Morvan T, Prieto‐Morin C, Mackowiak A, Manchon E, Hosseini H, Cordonnier C, Girard‐Buttaz I, Rosenstingl S, Hagel C, Kuhlenbaümer G, Leca‐Radu E, Goux D, Fleming L, Agtmael T, Chabriat H, Chapon F and Tournier‐Lasserve E (2016) Disruption of a mi R ‐29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy , Annals of Neurology, 10.1002/ana.24782, 80:5, (741-753), Online publication date: 1-Nov-2016. February 2016Vol 67, Issue 2 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.115.06220PMID: 26693817 Originally publishedDecember 22, 2015 PDF download Advertisement SubjectsHigh Blood PressureHypertension