Abstract 18446: Identification of a Novel Cellular Actor Participating in Vascular Remodeling During Pulmonary Arterial Hypertension : the PW1+ Progenitor Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
France Dierick
Keyword(s):  
Bone Marrow ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Bone Marrow Cells ◽  
Mouse Lung ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial ◽  
Lung Vessels

AIM: PW1+ progenitors were identified in various adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis is that PW1+ progenitors are recruited to participate in the vascular remodeling during pulmonary arterial hypertension (PAH). METHODS: PW1IRESnLacZ+/- mice express the β-galactosidase as a reporter gene for PW1 expression allowing to follow the lineage of PW1+ cells during a few days. These mice were exposed to chronic hypoxia (CH) to induce PAH, lung vessels neomuscularisation and SMC proliferation. PW1+ and β-Gal+ cells were studied by FACS and by immunofluorescence. RESULTS: PW1+ cells are localized in the lung parenchyma and in the perivascular zone in rodent and human lung. Two PW1+ populations were identified by flow cytometry in the mouse lung 1/ a Sca-1high/CD34high/PDGFR-α+ population which differentiates into calponin+ or α-SMA+ SMC and into vWF+ endothelial cell and 2/ a CD34-/CD146+ population expressing pericyte markers. After 2-4 days of CH, the number of lung PW1+ cells is increased (x3.5, p<0.01) and, in small pulmonary vessels media, the proportion of β-Gal+ SMC derived from PW1+ cells is increased (64±6% vs 35±3%, p<0.05) suggesting a recruitment and differentiation of PW1+ cells into lung vascular SMC. Moreover WT mice irradiated and engrafted with GFP+/β-Gal+ bone marrow cells do not show any increase in GFP+ SMC in lung vessels and do not show any β-Gal+ cells in the lung indicating that the lung PW1+ progenitors are not derived from bone marrow . Moreover, in the human PAH lung, PW1+ cells were observed in remodeled vascular structures: in the media of remodeled vessel and in plexiform lesions. CONCLUSION: These results suggest that lung resident PW1+ progenitors are recruited to participate in the vascular remodeling of small pulmonary vessels in experimental and human PAH. These progenitors show characteristics of pericytes and of vascular progenitors.

scholarly journals Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Blood ◽  
2012 ◽  
Vol 119 (7) ◽  
pp. 1772-1780 ◽  
Author(s):  
Jean-Marie Launay ◽  
Philippe Hervé ◽  
Jacques Callebert ◽  
Ziad Mallat ◽  
Corinne Collet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Progenitor Cells ◽  
Vascular Remodeling ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Differentiation Potential ◽  
Pulmonary Arterial ◽  
Marrow Cells

Abstract Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT2B, is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT2B receptors by circulating c-kit+ precursor cells, whereas mice lacking 5-HT2B receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT2B receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT2B receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34+ or mice c-kit+ progenitor cells in the presence of a 5-HT2B receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT2B receptors on bone marrow lineage progenitors is critical for the development of PAH.

scholarly journals AB1139 DIAGNOSTICIS AND PROGNOSTICIS SIGNIFICANCE OF CHEST CT EVALUATION OF SMALL PULMONARY VESSELS IN CONNECTIVE TISSUE DISEASES WITH PULMONARY ARTERIAL HYPERTENSION.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1859.1-1860
Author(s):  
Y. Zhang ◽  
N. Zhang ◽  
Y. Zhu ◽  
Q. Wang ◽  
L. Zhou
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Connective Tissue Diseases ◽  
Chest Ct ◽  
Pulmonary Vessels ◽  
Ct Evaluation ◽  
Pulmonary Arterial

Background:Pulmonary arterial hypertension (PAH) is a fatal complication of connective tissue diseases (CTDs). Chest CT has been increasingly used in the evaluation of patients with suspected PH noninvasively but there is a paucity of studies.Objectives:Our study was aimed to investigate the cross-sectional area (CSA) of small pulmonary vessels on chest CT for the diagnosis and prognosis of CTD-PAH.Methods:This retrospective study analyzed the data of thirty-four patients with CTD-PAH who were diagnosed by right heart catheterization (RHC) and underwent chest CT between March 2011 and October 2019. We measured the percentage of total CSA of vessels<5 mm2and 5-10 mm2as a percentage of total lung area (%CSA<5and %CSA5-10) on Chest CT. Furthermore, the association of %CSA with mean pulmonary artery pressure (mPAP) was also investigated. Besides, these patients were followed up until October 2019, and Kaplan-Meier survival curves were generated for the evaluation of prognosis.Results:Patients with CTD-PAH had significantly higher %CSA5-10than CTD-nPAH (p=0.001), %CSA5-10in CTD-S-PAH and IPAH was significantly higher than CTD-LM-PAH and COPD-PH (p<0.01). There was a positive correlation between %CSA5-10and mPAP in CTD-PAH (r=0.447, p=0.008). Considering %CSA5-10above 0.38 as a threshold level, the sensitivity and specificity were found to be 0.824 and 0.706, respectively. Patients with %CSA5-10≥0.38 had a lower survival rate than those with %CSA5-10<0.38 (p=0.049).Conclusion:Quantitative parameter, %CSA5-10on Chest CT might serve a crucial differential diagnostic tool for different types of PH. %CSA5-10≥0.38 is a prognostic indicator for evaluation of CTD-PAH.References:[1]Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177.[2]Siddiqui I, Rajagopal S, Brucker A, et al. Clinical and Echocardiographic Predictors of Outcomes in Patients With Pulmonary Hypertension. Am J Cardiol. 2018;122(5):872-878.[3]Coste F, Dournes G, Dromer C, et al. CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension. Thorax. 2016;71(9):830-837.[4]Freed BH, Collins JD, Francois CJ, et al. MR and CT Imaging for the Evaluation of Pulmonary Hypertension. JACC Cardiovasc Imaging. 2016;9(6):715-732.[5]Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):25S-32S.[6]Zanatta E, Polito P, Famoso G, et al. Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment. Exp Biol Med (Maywood). 2019;244(2):120-131.[7]Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165-175.[8]Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.[9]Thompson AAR, Lawrie A. Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. Trends Mol Med. 2017;23(1):31-45.[10]Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297-309.[11]Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012;122(12):4306-4313.[12]Seeger W, Adir Y, Barbera JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109-116.Acknowledgments:Thanks to all patients involved in this retrospective study. Thanks go to every participant who participated in this study for their enduring efforts in working with participants to complete the study. Thanks to Liangmin Wei for helping us with statistics analysis.Disclosure of Interests:None declared

scholarly journals LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension

2020 ◽  
Vol 319 (2) ◽  
pp. H377-H391 ◽  
Author(s):  
Si Lei ◽  
Fei Peng ◽  
Mei-Lei Li ◽  
Wen-Bing Duan ◽  
Cai-Qin Peng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Long Noncoding Rna ◽  
Vascular Remodeling ◽  
Noncoding Rna ◽  
In Vivo Models ◽  
Pulmonary Arterial

Smooth muscle-enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.

Abstract 16770: The Epigenetic Modifier EP300: A New Corner Stone in the Regulation of Both Vascular Remodeling and Right Ventricle Failure in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Alice Bourgeois ◽  
Sarah-Eve Lemay ◽  
Yann Grobs ◽  
Charlotte romanet ◽  
Junichi Omura ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Annexin V ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Pulmonary Arterial

Introduction: Pulmonary Arterial Hypertension (PAH) is characterized by excessive proliferation and resistance to apoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs), leading to progressive increases in pulmonary vascular resistance, and ultimately right ventricular (RV) failure and death. Thanks to omics technologies, we made tremendous progress in understanding gene misregulation during disease processes and identified the epigenetic factor EP300 as a critical player in pathological processes like proliferation/apoptosis and hypertrophy/fibrosis all of which are critical features of both PA remodeling and RV failure in PAH. We hypothesized that EP300 is upregulated in PAH and contributes to both PA remodeling and RV failure. Methods and Results: By Western blot (WB) and immunofluorescence (IF), we found that EP300 is up-regulated in isolated PASMCs and distal PAs from PAH patients (n=11-14) compared to controls (n=8-10) (p<0.01). Similar results were observed in 3 PAH animal models, namely the monocrotaline (MCT), the Sugen/Hypoxia (Su/Hx) and the Fawn-Hooded rat (FHR) (p<0.05). In vitro, pharmacological inhibition of EP300 using CCS-1477 reduces PAH-PASMC proliferation (Ki67 labeling & WB PCNA; p<0.05) and resistance to apoptosis (Annexin V assay & WB Survivin; p<0.05). These effects were confirmed at the molecular level by RNA-Seq analysis. In addition, increased EP300 expression was observed in hypertrophied and failed RV from PAH patients, as well as in rats injected with MCT or subjected to pulmonary artery banding (WB, p<0.05). In animal models, EP300 negatively correlates with CO and positively correlates with RVEDP, cardiomyocyte surface area and fibrosis. Finally, we demonstrated that inhibition of EP300 using CCS-1477 or SGC-CBP30 significantly improved established PAH (right heart catheterization) in two animal models (MCT and FHR). Conclusion: EP300 upregulation contributes to both pulmonary vascular remodeling and RV dysfunction seen in PAH and its inhibition represents a promising therapeutic avenue.

scholarly journals Skeletal muscle mitochondrial oxidative phosphorylation function in idiopathic pulmonary arterial hypertension: in vivo and in vitro study

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401876829 ◽  
Author(s):  
Sasiharan Sithamparanathan ◽  
Mariana C. Rocha ◽  
Jehill D. Parikh ◽  
Karolina A. Rygiel ◽  
Gavin Falkous ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Oxidative Phosphorylation ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial

Mitochondrial dysfunction within the pulmonary vessels has been shown to contribute to the pathology of idiopathic pulmonary arterial hypertension (IPAH). We investigated the hypothesis of whether impaired exercise capacity observed in IPAH patients is in part due to primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle. This could lead to potentially new avenues of treatment beyond targeting the pulmonary vessels. Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. 31P-MRS showed abnormal skeletal muscle bioenergetics with prolonged recovery times of phosphocreatine and abnormal muscle pH handling. Histochemistry and quadruple immunofluorescence performed on muscle biopsies showed normal function and subunit protein abundance of the complexes within the OXPHOS system. Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction but raises the possibility of impaired oxygen delivery to the mitochondria affecting skeletal muscle bioenergetics during exercise.

scholarly journals Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

2017 ◽  
Vol 8 (1) ◽  
pp. 204589321774142 ◽  
Author(s):  
Valerie Nadeau ◽  
Francois Potus ◽  
Olivier Boucherat ◽  
Renee Paradis ◽  
Eve Tremblay ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Skeletal Muscles ◽  
Cell Metabolism ◽  
Critical Role ◽  
Capillary Density ◽  
Pulmonary Hemodynamics ◽  
Pulmonary Arterial

Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ETA/ETB receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH–PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ETA/ETB receptor blockade improved the metabolic changes involved in PAH-PASMCs’ proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles.

Abstract 17072: Acetylcholine Signaling and Endothelial to Mesenchymal Transition in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ana Fernandez Nicolas ◽  
Alexander Vang ◽  
Thomas Mancini ◽  
Denielli da Silva Goncalves Bos ◽  
Richard T Clements ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Smooth Muscle Actin ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Α7 Nachr ◽  
Pulmonary Arterial ◽  
Dual Staining

Introduction: Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling. Transition of endothelial cells (EC) to mesenchymal cells (EndMT) contributes to vascular remodeling; however, the role of EndMT and underlying mechanisms in PAH remain unclear. While nicotinic acetylcholine (Ach) receptor (nAChR)-mediated pathway regulates epithelial to mesenchymal transition and promotes mesenchymal cell proliferation, its role in EndMT is unknown. In this study, we investigate EndMT in PAH and delineate the mechanisms. Methods: PAH was induced in Sprague Dawley rats by SU5416 (20 mg/kg; s.c.), followed by 3 wks of hypoxia (3 wk PAH) or 3wks of hypoxia with additional 4 wks of normoxia (7 wk PAH). Rats without SU5416 and kept at normoxia served as controls. At the end of experiments, hemodynamic measurements were performed. Lung EC were then isolated and purified using CD31 antibody conjugated beads and passage 3-4 were used. EndMT was assessed by dual staining of EC markers (von Willebrand factor and Griffonia simplicifolia) and α-smooth muscle actin (α-SMA) and by the mRNA expression of EC and mesenchymal genes. Lung ACh was measured by ELISA. Results: PAH rats had elevated PA pressures at both 3 wk (PAH vs. CON in mm Hg: 77.3 vs. 24.8, p<0.05, n=4-5) and 7 wk (65.5 vs. 28.6, p<0.05, n=10-12). EndMT was evidenced in PAH (% of cells positive with both EC markers and α- SMA: 3 wks: PAH 4.2% vs. CON 1.6%, p<0.05; 7 wks: PAH 38.5% vs. CON 4.5%, p<0.05), which was associated with significantly increased expression of mesenchymal gene (CD44, PAI1, and α-SMA) and decreased expression of vascular endothelial cadherin at 7 wk. The lungs of PAH rats had higher levels of ACh (PAH vs. CON in pg/mL, 3wk: 78.7 vs. 47.3, p<0.05, n=7; 7wk: 85.1 vs. 45.6, p<0.05, n=7). A significant increase in α7 nAChR expression was found in 7wk PAH EC. In vitro , treatment with ACh markedly induced EndMT in lung EC from normal rats, which was assessed by increased dual staining of EC markers and α-SMA and increased expression of mesenchymal genes (α-SMA, PAI1, and pro-collagen 1, p<0.05 for all). Conclusions: EndMT in PAH is associated with increased lung ACh levels and α7nAChR expression in lung ECs. ACh/nAChR-mediated EndMT may contribute to the vascular remodeling in PAH.

scholarly journals MiR-193-3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402097491
Author(s):  
Zhenhua Wu ◽  
Jie Geng ◽  
Yujuan Qi ◽  
Jian Li ◽  
Yaobang Bai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs). To explore the potential mechanism of miR-193-3p in pulmonary arterial hypertension, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and p21-activated protein kinase 4 (PAK4) in the lung samples of PAH patients and paired healthy samples from the healthy subjects in PHA cells and rats were detected by quantitative reverse transcriptase-PCR. Morphological changes in lung tissues were determined using hematoxylin and eosin staining. Right ventricular systolic pressure (RVSP) and ratio of right ventricle to left ventricle plus septum (RV/LV p S) were measured. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, and migration were detected by 3-(4, 5-Dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) flow cytometry, and wound-healing assays, respectively. The protein expressions of PAK4, proliferating cell nuclear antigen (PCNA), P21, p-AKT, and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in pulmonary arterial hypertension, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia condition promoted cell proliferation, migration, and inhibited apoptosis accompanied with increased expressions of PCNA and p-AKT/AKT and decreased expression of P21 in PASMCs. MiR-193-3p overexpression attenuated the effects of hypoxia on PASMCs via downregulating PAK4. Monocrotaline treatment increased p-AKT/AKT and decreased P21 expression and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT, and increased P21 levels via downregulating PAK4 in monocrotaline-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregulating PAK4.

scholarly journals Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (23) ◽  
pp. 9222
Author(s):  
William Gerthoffer
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Small Molecules ◽  
Vascular Remodeling ◽  
Arterial Wall ◽  
Vascular Wall ◽  
Wall Structure ◽  
Wall Thickening ◽  
Pulmonary Arterial

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

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