Resident cell lineages are preserved in pulmonary vascular remodeling (original) (raw)
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International Journal of Environmental Research and Public Health, 2021
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.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2020
Excessive accumulation of resident cells within the pulmonary vascular wall represents the hallmark feature of the remodeling occurring in pulmonary arterial hypertension (PAH). Furthermore, we have previously demonstrated that pulmonary arterioles are excessively covered by pericytes in PAH, but this process is not fully understood. The aim of our study was to investigate the dynamic contribution of pericytes in PAH vascular remodeling. APPROACH AND RESULTS: In this study, we performed in situ, in vivo, and in vitro experiments. We isolated primary cultures of human pericytes from controls and PAH lung specimens then performed functional studies (cell migration, proliferation, and differentiation). In addition, to follow up pericyte number and fate, a genetic fate-mapping approach was used with an NG2CreER;mT/mG transgenic mice in a model of pulmonary arteriole muscularization occurring during chronic hypoxia. We identified phenotypic and functional abnormalities of PAH pericytes in vitro, as they overexpress CXCR (C-X-C motif chemokine receptor)-7 and TGF (transforming growth factor)-βRII and, thereby, display a higher capacity to migrate, proliferate, and differentiate into smooth muscle-like cells than controls. In an in vivo model of chronic hypoxia, we found an early increase in pericyte number in a CXCL (C-X-C motif chemokine ligand)-12-dependent manner whereas later, from day 7, activation of the canonical TGF-β signaling pathway induces pericytes to differentiate into smooth muscle-like cells. CONCLUSIONS: Our findings reveal a pivotal role of pulmonary pericytes in PAH and identify CXCR-7 and TGF-βRII as 2 intrinsic abnormalities in these resident progenitor vascular cells that foster the onset and maintenance of PAH structural changes in blood lung vessels. VISUAL OVERVIEW: An online visual overview is available for this article.
Microvascular Research, 2004
Pulmonary artery vasoconstriction and vascular remodeling greatly contribute to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH). The development of PAH involves a complex and heterogeneous constellation of multiple genetic, molecular, and humoral abnormalities, which interact in a complicated manner, presenting a final manifestation of vascular remodeling in which fibroblasts, smooth muscle and endothelial cells, and platelets all play a role. Vascular remodeling is characterized largely by medial hypertrophy due to enhanced vascular smooth muscle cell proliferation or attenuated apoptosis and to endothelial cell over-proliferation, which can result in lumen obliteration. In addition to other factors, cytoplasmic Ca2+ in particular seems to play a central role as it is involved in both the generation of force through its effects on the contractile machinery, and the initiation and propagation of cell proliferation via its effects on transcription factors, mitogens, and cell cycle components. This review focuses on the role played by cellular factors, circulating factors, and genetic molecular signaling factors that promote a proliferative, antiapoptotic, and vasoconstrictive physiological milieu leading to vascular remodeling.
Cellular and Molecular Basis of Pulmonary Arterial Hypertension
Journal of the American College of Cardiology, 2009
Pulmonary arterial hypertension (PAH) is caused by functional and structural changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance. The process of pulmonary vascular remodeling is accompanied by endothelial dysfunction, activation of fibroblasts and smooth muscle cells, crosstalk between cells within the vascular wall, and recruitment of circulating progenitor cells. Recent findings have reestablished the role of chronic vasoconstriction in the remodeling process. Although the pathology of PAH in the lung is well known, this article is concerned with the cellular and molecular processes involved. In particular we focus on the role of the Rho family guanosine triphosphatases in endothelial function and vasoconstriction. The crosstalk between endothelium and vascular smooth muscle is explored in the context of mutations in the bone morphogenetic protein type II receptor, alterations in angiopoietin-1/TIE2 signaling and the serotonin pathway. We also review the role of voltage-gated K + (Kv) channels and transient receptor potential channels in the regulation of cytosolic [Ca 2+ ] and [K + ], vasoconstriction, proliferation and cell survival. We highlight the importance of the extracellular matrix as an active regulator of cell behavior and phenotype and evaluate the contribution of the glycoprotein tenascin-c as a key mediator of smooth muscle cell growth and survival. Finally, we discuss the origins of a cell type critical to the process of pulmonary vascular remodeling, the myofibroblast, and review the evidence supporting a contribution for the involvement of endothelial-mesenchymal transition and recruitment of circulating mesenchymal progenitor cells.
Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension
2016
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.115.307035 Rationale: Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1+ progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro. Objective: To determine the role of pulmonary PW1+ progenitor cells in vascular remodeling characteristic of
Circulation Research, 2016
P ulmonary arterial hypertension (PAH), a rare and severe disease with no curative options, is characterized by a sustained increase in pulmonary vascular resistance leading to right heart failure and death. 1 Histologically, PAH is associated with neomuscularization of small pulmonary vessels, medial hypertrophy, neointima formation, endothelial proliferation, excessive extracellular matrix deposition, and recruitment of inflammatory cells in the vascular wall. 2-4 To date, the cellular origin of neomuscularization and medial hypertrophy remains unknown. It was proposed that new smooth muscle cells (SMCs) are derived from resident SMC that re-enter a proliferative state 5 or from pericytes 6,7 and from endothelial cells that adopt a smooth muscle fate. 8 Recent studies suggest that SMCs originate from the proliferation and differentiation of either resident or circulating bone marrow (BM)-derived progenitor cells. 9 Indeed,
Circulation Research, 2016
Rationale: Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1 + progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro. Objective: To determine the role of pulmonary PW1 + progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension. Methods and Results: We investigated their contribution during chronic hypoxia–induced vascular remodeling in Pw1 nLacZ+/− mouse expressing β-galactosidase in PW1 + cells and in differentiated cells derived from PW1 + cells. PW1 + progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1 + cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1 + cells and the proportion of β-gal + vascular SMC were increased, indicating a recruitment of PW1 + cells and their different...
New Molecular Targets of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension
CHEST Journal, 2015
Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained infl ammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant infl ammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more eff ective approaches for PAH treatment. CHEST 2015; 147 (2): 529-537 ABBREVIATIONS: 5-HT 5 serotonin; AngII 5 angiotensin II; BMPRII 5 bone morphogenetic protein receptor II; EC 5 endothelial cell; ECM 5 extracellular matrix; ET 5 endothelin; FGF 5 fi broblast growth factor; MCP 5 monocyte chemoattractant protein; MIF 5 migration inhibitory factor; miRNA 5 microRNA; MMP 5 matrix metalloproteinase; mPAP 5 mean pulmonary arterial pressure; NO 5 nitric oxide; PAH 5 pulmonary arterial hypertension; PGI2 5 prostacyclin; PH 5 pulmonary hypertension; SMC 5 smooth muscle cell; TGF 5 transforming growth factor; Treg 5 regulatory T lymphocyte
Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling
International Journal of Molecular Sciences, 2022
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development.
Recapitulation of Developing Artery Muscularization in Pulmonary Hypertension
Excess smooth muscle accumulation is a key component of many vascular disorders, including atherosclerosis, restenosis, and pulmonary artery hypertension, but the underlying cell biological processes are not well defined. In pulmonary artery hypertension, reduced pulmonary artery compliance is a strong independent predictor of mortality, and pathological distal arteriole muscularization contributes to this reduced compliance. We recently demonstrated that embryonic pulmonary artery wall morphogenesis consists of discrete developmentally regulated steps. In contrast, poor understanding of distal arteriole muscularization in pulmonary artery hypertension severely limits existing therapies that aim to dilate the pulmonary vasculature but have modest clinical benefit and do not prevent hypermuscularization. Here, we show that most pathological distal arteriole smooth muscle cells, but not alveolar myofibroblasts, derive from pre-existing smooth muscle. Furthermore, the program of distal arteriole muscularization encompasses smooth muscle cell dedifferentiation, distal migration, proliferation, and then redifferentiation, thereby recapitulating many facets of arterial wall development.