{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:14:37Z","timestamp":1760235277773,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,14]],"date-time":"2021-08-14T00:00:00Z","timestamp":1628899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BE4443\/1-1, BE4443\/4-1, BE4443\/6-1, KFO309 P7, SFB1213-projects A02 and A04, EL 931\/4-1"],"award-info":[{"award-number":["BE4443\/1-1, BE4443\/4-1, BE4443\/6-1, KFO309 P7, SFB1213-projects A02 and A04, EL 931\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Vascular remodeling is a prominent feature of pulmonary hypertension. This process involves increased muscularization of already muscularized vessels as well as neo-muscularization of non-muscularized vessels. The cell-of-origin of the newly formed vascular smooth muscle cells has been a subject of intense debate in recent years. Identifying these cells may have important clinical implications since it opens the door for attempts to therapeutically target the progenitor cells and\/or reverse the differentiation of their progeny. In this context, the dominant model is that these cells derive from pre-existing smooth muscle cells that are activated in response to injury. In this mini review, we present the evidence that is in favor of this model and, at the same time, highlight other studies indicating that there are alternative cellular sources of vascular smooth muscle cells in pulmonary vascular remodeling.<\/jats:p>","DOI":"10.3390\/ijerph18168584","type":"journal-article","created":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T21:43:55Z","timestamp":1629063835000},"page":"8584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evidence for Multiple Origins of De Novo Formed Vascular Smooth Muscle Cells in Pulmonary Hypertension: Challenging the Dominant Model of Pre-Existing Smooth Muscle Expansion"],"prefix":"10.3390","volume":"18","author":[{"given":"Xuran","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany"},{"name":"School of Pharmacy, Wenzhou Medical University, Wenzhou 325015, China"},{"name":"Department of Internal Medicine, Institute for Lung Health (ILH), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8970-8299","authenticated-orcid":false,"given":"Negah","family":"Ahmadvand","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-San","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany"},{"name":"Department of Internal Medicine, Institute for Lung Health (ILH), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saverio","family":"Bellusci","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-3417","authenticated-orcid":false,"given":"Elie","family":"El Agha","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany"},{"name":"Department of Internal Medicine, Institute for Lung Health (ILH), Justus-Liebig University, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/eurheartj\/ehv317","article-title":"2015 ESC\/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology (ESC) and the european respiratory society (ERS): Endorsed by: Association for european paediatric and congenital cardiology (AEPC), International society for heart and lung transplantation (ISHLT)","volume":"37","author":"Humbert","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1801887","DOI":"10.1183\/13993003.01887-2018","article-title":"Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives","volume":"53","author":"Humbert","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nrcardio.2011.87","article-title":"Mechanisms of disease: Pulmonary arterial hypertension","volume":"8","author":"Schermuly","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"H1322","DOI":"10.1152\/ajpheart.00136.2018","article-title":"Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension","volume":"315","author":"Thenappan","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1701214","DOI":"10.1183\/13993003.01214-2017","article-title":"The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension","volume":"51","author":"Marsh","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1164\/rccm.201608-1630PP","article-title":"The Roles of Immunity in the prevention and evolution of pulmonary arterial hypertension","volume":"195","author":"Nicolls","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108549","DOI":"10.1016\/j.celrep.2020.108549","article-title":"Identification of a repair-supportive mesenchymal cell population during airway epithelial regeneration","volume":"33","author":"Moiseenko","year":"2020","journal-title":"Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4409","DOI":"10.1172\/JCI58097","article-title":"Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury","volume":"121","author":"Volckaert","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_9","first-page":"296","article-title":"Fgf10-positive cells represent a progenitor cell population during lung development and postnatally","volume":"141","author":"Herold","year":"2014","journal-title":"Dev. Camb. Engl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/dvdy.24504","article-title":"Ex Vivo Analysis of the contribution of FGF10+ cells to airway smooth muscle cell formation during early lung development","volume":"246","author":"Kheirollahi","year":"2017","journal-title":"Dev. Dyn."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/path.5044","article-title":"Resident cell lineages are preserved in pulmonary vascular remodeling","volume":"244","author":"Crnkovic","year":"2018","journal-title":"J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.celrep.2014.01.042","article-title":"Recapitulation of developing artery muscularization in pulmonary hypertension","volume":"6","author":"Sheikh","year":"2014","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"308ra159","DOI":"10.1126\/scitranslmed.aaa9712","article-title":"Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension","volume":"7","author":"Sheikh","year":"2015","journal-title":"Sci. Transl. Med."},{"doi-asserted-by":"crossref","unstructured":"Ntokou, A., Dave, J.M., Kauffman, A.C., Sauler, M., Ryu, C., Hwa, J., Herzog, E.L., Singh, I., Saltzman, W.M., and Greif, D.M. (2021). Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension. JCI Insight, 6.","key":"ref_14","DOI":"10.1172\/jci.insight.139067"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1161\/CIRCULATIONAHA.120.045750","article-title":"A notch3-marked subpopulation of vascular smooth muscle cells is the cell of origin for occlusive pulmonary vascular lesions","volume":"142","author":"Steffes","year":"2020","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1242\/jcs.103.2.521","article-title":"Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells In Vitro","volume":"103","author":"Arciniegas","year":"1992","journal-title":"J. Cell Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1161\/01.RES.0000021432.70309.28","article-title":"Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: In Vitro analysis","volume":"90","author":"Frid","year":"2002","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1161\/CIRCULATIONAHA.114.008750","article-title":"Endothelial-to-mesenchymal transition in pulmonary hypertension","volume":"131","author":"Ranchoux","year":"2015","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1161\/CIRCULATIONAHA.115.020617","article-title":"In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug","volume":"133","author":"Hopper","year":"2016","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1161\/CIRCULATIONAHA.113.003734","article-title":"Endothelial fate mapping in mice with pulmonary hypertension","volume":"129","author":"Qiao","year":"2014","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"L118","DOI":"10.1152\/ajplung.00296.2017","article-title":"Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension","volume":"314","author":"Suzuki","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/1465-9921-12-109","article-title":"Endothelial-like cells in chronic thromboembolic pulmonary hypertension: Crosstalk with myofibroblast-like cells","volume":"12","author":"Sakao","year":"2011","journal-title":"Respir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.devcel.2012.07.009","article-title":"Radial construction of an arterial wall","volume":"23","author":"Greif","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_24","first-page":"909","article-title":"Pericytes. morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche","volume":"24","author":"Madrid","year":"2009","journal-title":"Histol. Histopathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.stem.2017.07.011","article-title":"Mesenchymal Stem cells in fibrotic disease","volume":"21","author":"Kramann","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"621","DOI":"10.3390\/cells2030621","article-title":"Pericytes, mesenchymal stem cells and the wound healing process","volume":"2","author":"Mills","year":"2013","journal-title":"Cells"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1161\/CIRCULATIONAHA.113.007469","article-title":"Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension","volume":"129","author":"Ricard","year":"2014","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1161\/ATVBAHA.119.313715","article-title":"Lineage tracing reveals the dynamic contribution of pericytes to the blood vessel remodeling in pulmonary hypertension","volume":"40","author":"Bordenave","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9349","DOI":"10.1073\/pnas.0711382105","article-title":"A sonic hedgehog signaling domain in the arterial adventitia supports resident sca1+ smooth muscle progenitor cells","volume":"105","author":"Passman","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.stem.2008.07.003","article-title":"A perivascular origin for mesenchymal stem cells in multiple human organs","volume":"3","author":"Crisan","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.stem.2014.11.004","article-title":"Perivascular gli1+ progenitors are key contributors to injury-induced organ fibrosis","volume":"16","author":"Kramann","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.stem.2017.03.008","article-title":"Gli1+ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target","volume":"20","author":"Schneider","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.stem.2016.08.001","article-title":"Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease","volume":"19","author":"Kramann","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/stem.1911","article-title":"Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm","volume":"33","author":"Li","year":"2015","journal-title":"Stem Cells Dayt. Ohio"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/stem.2615","article-title":"Origin and characterization of alpha smooth muscle actin-positive cells during murine lung development","volume":"35","author":"Moiseenko","year":"2017","journal-title":"Stem Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1161\/CIRCRESAHA.115.307035","article-title":"Resident PW1+ progenitor cells participate in vascular remodeling during pulmonary arterial hypertension","volume":"118","author":"Dierick","year":"2016","journal-title":"Circ. Res."},{"key":"ref_37","first-page":"2879","article-title":"Defining skeletal muscle resident progenitors and their cell fate potentials","volume":"140","author":"Formicola","year":"2013","journal-title":"Dev. Camb. Engl."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"L363","DOI":"10.1152\/ajplung.00212.2011","article-title":"The monocrotaline model of pulmonary hypertension in perspective","volume":"302","author":"Farkas","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/path.1711020205","article-title":"Hypertensive pulmonary vascular disease in rats after prolonged feeding with crotalaria spectabilis seeds","volume":"102","author":"Smith","year":"1970","journal-title":"J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"L715","DOI":"10.1152\/ajplung.00086.2009","article-title":"Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and no scavenging","volume":"297","author":"Lee","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"H1943","DOI":"10.1152\/ajpheart.00642.2008","article-title":"Depletion of the atpase nsf from golgi membranes with hypo-s-nitrosylation of vasorelevant proteins in endothelial cells exposed to monocrotaline pyrrole","volume":"295","author":"Mukhopadhyay","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ccm.2006.11.010","article-title":"Pathology of pulmonary hypertension","volume":"28","author":"Tuder","year":"2007","journal-title":"Clin. Chest Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1093\/cvr\/cvy004","article-title":"Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension","volume":"114","author":"Stenmark","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_44","first-page":"51","article-title":"Hypoxia and incorporation of 3h-thymidine by cells of the rat pulmonary arteries and alveolar wall","volume":"96","author":"Meyrick","year":"1979","journal-title":"Am. J. Pathol."},{"key":"ref_45","first-page":"37","article-title":"Development of pulmonary arterial changes in rats fed crotalaria spectabilis","volume":"94","author":"Meyrick","year":"1979","journal-title":"Am. J. Pathol."},{"key":"ref_46","first-page":"209","article-title":"Pulmonary arteries of the normal rat: The thick walled oblique muscle segment","volume":"125","author":"Meyrick","year":"1978","journal-title":"J. Anat."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"30336","DOI":"10.1074\/jbc.273.46.30336","article-title":"Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3\u2019-kinase\/akt signal transduction pathway. requirement for Flk-1\/KDR activation","volume":"273","author":"Gerber","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/nm1095-1024","article-title":"Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity","volume":"1","author":"Alon","year":"1995","journal-title":"Nat. Med."},{"key":"ref_49","first-page":"99","article-title":"SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1\/KDR) That inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types","volume":"59","author":"Fong","year":"1999","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"L1013","DOI":"10.1152\/ajplung.00217.2009","article-title":"Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure","volume":"297","author":"Stenmark","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1096\/fj.00-0343com","article-title":"Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension","volume":"15","author":"Kasahara","year":"2001","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1161\/CIRCULATIONAHA.109.927681","article-title":"Formation of plexiform lesions in experimental severe pulmonary arterial hypertension","volume":"121","author":"Abe","year":"2010","journal-title":"Circulation"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"L238","DOI":"10.1152\/ajplung.90591.2008","article-title":"Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment","volume":"297","author":"Burke","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/18\/16\/8584\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:45:58Z","timestamp":1760165158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/18\/16\/8584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,14]]},"references-count":53,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijerph18168584"],"URL":"https:\/\/doi.org\/10.3390\/ijerph18168584","relation":{},"ISSN":["1660-4601"],"issn-type":[{"type":"electronic","value":"1660-4601"}],"subject":[],"published":{"date-parts":[[2021,8,14]]}}}