Rapamycin Reverses Pulmonary Artery Smooth Muscle Cell Proliferation in Pulmonary Hypertension

Houssaïni, Amal; Abid, Shariq; Mouraret, Nathalie; Wan, Feng; Rideau, Dominique; Saker, Mirna; Marcos, Élisabeth; Tissot, Claire-Marie; Dubois‐Randé, Jean‐Luc; Amsellem, Valérie; Adnot, Serge

doi:10.1165/rcmb.2012-0429oc

Cited by 131 publications

(115 citation statements)

References 26 publications

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“…Consequently, we have shown that ECs are a source for α-SMA-positive cells that build up PAH vascular lesions, and that alteration in the BMPR2 axis could be a possible cause rather than a consequence of EndoMT. Moreover, we suggest that the curative effects of rapamycin or rapamycin derivatives observed in several PH models 21,31,32 may implicate a partial inhibition of EndoMT.…”

Section: Bmpr2mentioning

confidence: 79%

“…When used between day 21 and day 28 (in a curative approach applied on an established PH), rapamycin (5 mg/kg) reduced mean pulmonary artery pressure and the Fulton index, and normalized the muscularization of the pulmonary artery in comparison with MCT alone. 21 The analysis of the Twist-1, p120-catenin, and VE-cadherin levels in the lungs of those rats revealed that rapamycin reduced to basal the pulmonary level of Twist-1, and increased the level of p120-catenin, without significant reexpression of VE-cadherin ( Figure IVA and IVB in the online-only Data Supplement). Hence, the curative effects of rapamycin in MCT-induced PH may implicate a partial inhibition of EndoMT.…”

Section: Endomt In Pah Animal Modelmentioning

confidence: 93%

“…[20][21][22] PH was induced in rats by MCT (60 mg/kg) 20,21 or by the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockage with Sugen (SuHx model). 22 We had access to the tissues from different time points of PH development (kinetic of MCT-induced PH development) 20 and from rats exposed to MCT and rapamycin (5 mg/kg from day 21 to 28).…”

Section: Rat Specimens and In Vivo Study Designmentioning

confidence: 99%

“…22 We had access to the tissues from different time points of PH development (kinetic of MCT-induced PH development) 20 and from rats exposed to MCT and rapamycin (5 mg/kg from day 21 to 28). 21 Hemodynamic data (mean pulmonary artery pressure) and right ventricular morphology (Fulton Index) were available from animals of the kinetic study (unpublished data that served in setting up the experiments). The SuHx model is a severe angio-obliterative PH model that reproduces multiple salient histological features of human PAH 23 (see the online-only Data Supplement).…”

Section: Rat Specimens and In Vivo Study Designmentioning

confidence: 99%

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Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

et al. 2015

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P ulmonary arterial hypertension (PAH) is a rare disorder, with a prevalence of 15 to 50 patients per million in the population. It is characterized by remodeling of the precapillary pulmonary arteries, with endothelial cell dysfunction contributing to endothelial and pulmonary artery smooth muscle cell proliferation. This remodeling increases pulmonary vascular resistance and pulmonary arterial pressure (mean pulmonary arterial pressure ≥25 mm Hg and a pulmonary capillary wedge Background-The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of α-smooth muscle actin-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-smooth muscle actin-expressing cells. Methods and Results-In situ evidence of EndoMT in human PAH was obtained by using confocal microscopy of multiple fluorescent stainings at the arterial level, and by using transmission electron microscopy and correlative light and electron microscopy at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells. In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative real-time polymerase chain reaction and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (monocrotaline and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2 Δ140Ex1/+ rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH, and decreased the migration of human pulmonary artery endothelial cells, providing the proof of concept that EndoMT is druggable. Conclusions-EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vas cular remodeling of PAH, findings that may have therapeutic implications.

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Section: Bmpr2mentioning

confidence: 79%

Section: Endomt In Pah Animal Modelmentioning

confidence: 93%

Section: Rat Specimens and In Vivo Study Designmentioning

confidence: 99%

Section: Rat Specimens and In Vivo Study Designmentioning

confidence: 99%

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Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

et al. 2015

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“…It was not surprising that Akt (protein kinase B), a critical component of vascular remodeling in PAH (35), is a key mediator of Sfrp-2 expression (49). Here we directly link decreased BMP signaling and the mechanical properties of the vasculature to regulation of Sfrp-2 transcript expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

West

Austin

Gaskill

et al. 2014

American Journal of Physiology-Cell Physiology

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May 28, 2014; doi:10.1152/ajpcell.00057.2014.-Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. pulmonary arterial hypertension; gene array; induced pluripotent stem cell; mesenchymal stromal cell; endothelial cell; heritable pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; Wnt signaling PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by vascular remodeling, including endothelial cell (EC) dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. More recently, the contribution of multipotent mesenchymal stromal cells (MSC) to muscularization of microvessels has been described (13). The interactions between the lung microenvironment, vascular EC, and MSC during remodeling in PAH remain unclear. All forms of PAH have a high mortality rate, despite current therapeutic options.Deregulated bone morphogenetic protein (BMP) receptor type II (BMPR2) signaling is strongly associated with the development of PAH in both heritable (BMPR2 mut and Cav1 mut ) and idiopathic cases, although the molecular mechanisms through which BMPR2 derangement promotes PAH are unknown. Unfortunately, most rodent models of PAH do not precisely recapitulate the disease pathology; these models display less substantial pulmonary vascular remodeling in both proximal arteries and distal microvasculature, significantly slowing drug discovery efforts. Current in vitro models overexpressing mutant BMPR2 in cell types of interest are complicated by persistent retention of wild-type (WT) signaling. Moreover, human PAH tissue is limited in quantity, and specimens are typically obtained posttransplant or at autopsy, which limits conclusions about disease initiation and propagation. Previous global gene expression analyses using patient samples to identify risk factors for PAH have ...

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