A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects

Gomez-Arroyo, José; Saleem, Sheinei J.; Mizuno, Shiro; Syed, Aamer; Bogaard, Harm Jan; Abbate, Antonio; Taraseviciene‐Stewart, Laimute; Sung, Yon K.; Kraskauskas, Donatas; Farkas, Daniela; Conrad, Daniel H.; Nicolls, Mark R.; Voelkel, Norbert F.

doi:10.1152/ajplung.00362.2011

Cited by 176 publications

(159 citation statements)

References 125 publications

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“…Baseline RVSP measurements in wt-unchallenged mice can vary from 10 to 20 mmHg up to 22 mmHg and up to 35 mmHg after chronic hypoxia exposure. 31 Our data show a modest increase in the RVSP values (from 21 to 25.5 mmHg), only 20 days of EH ITSN treatment under normoxic conditions. This relatively short duration of treatment with the myc-EH ITSN fragment with no chronic hypoxia and/or chemical exposure may explain the weak correlation between the severity of vascular remodeling and hemodynamic measurements.…”

Section: Treatment Of K0mentioning

confidence: 43%

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Patel

Predescu

Bardita

et al. 2017

The American Journal of Pathology

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Murine models of pulmonary arterial hypertension (PAH) that recapitulate the plexiform and obliterative arteriopathy seen in PAH patients and help in defining the molecular mechanisms involved are missing. Herein, we investigated whether intersectin-1s (ITSN) deficiency and prolonged lung expression of an ITSN fragment with endothelial cell (EC) proliferative potential (EH ITSN ), present in the lungs of PAH animal models and human patients, induce formation of plexiform/obliterative lesions and defined the molecular mechanisms involved. ITSN-deficient mice (knockout/heterozygous and knockdown) were subjected to targeted lung delivery of EH ITSN via liposomes for 20 days. Immunohistochemistry and histological and morphometric analyses revealed a twofold increase in proliferative ECs and a 1.35-fold increase in proliferative a-smooth muscle actinepositive cells in the lungs of ITSNdeficient mice, transduced with the EH ITSN relative to wild-type littermates. Treated mice developed severe medial wall hypertrophy, intima proliferation, and various forms of obliterative and plexiformlike lesions in pulmonary arteries, similar to PAH patients. Hemodynamic measurements indicated modest increases in the right ventricular systolic pressure and right ventricle hypertrophy. Transcriptional and protein assays of lung tissue indicated p38 MAPK -dependent activation of Elk-1 transcription factor and increased expression of c-Fos gene. This unique murine model of PAH-like plexiform/obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provides novel druggable targets to ameliorate and, perhaps, reverse the EC plexiform phenotype in severe human PAH. Pulmonary arterial hypertension (PAH) is a severe human disease characterized by narrowing of the small pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance, which frequently leads to right-sided heart failure and death.1e3 A common histological finding in patients with severe PAH is the presence of plexiform lesions that obliterate the small to mid-sized pulmonary arterioles. 4,5 The plexiform pulmonary vascular lesions found at branching points in the small pulmonary arterioles are lumen-obliterating, glomeruloid-like vascular structures, predominantly composed of actively dividing and phenotypically abnormal apoptosis-resistant endothelial cells (ECs).6,7 The cellular and molecular mechanisms responsible for the development of plexiform lesions are poorly understood.Recent evidence suggests the involvement of inflammatory mechanisms in the development of PAH. 8 Studies have indicated that inflammation associated with human PAH Supported by NIH grants R01 HL089462 (S.P.) and R01 HL0127022 (S.P.).Disclosures: None declared.

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Section: Treatment Of K0mentioning

confidence: 43%

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Patel

Predescu

Bardita

et al. 2017

The American Journal of Pathology

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“…As a result, numerous animal models can be used to study PAH (28). Unfortunately, fundamental pathophysiological differences exist between PAH and COPD-associated PH (11), and these differences preclude using animal models of PAH to study PH in COPD.…”

Section: Discussionmentioning

confidence: 99%

“…These changes include increased vascular smooth muscle mass and the neomuscularization of previously nonmuscular vessels, leading to vessel occlusion (28). In our study, lung sections of patients diagnosed with COPD, with or without a secondary diagnosis of PH, were stained with a-SMA.…”

Section: Vascular Remodeling In Patients With Copdmentioning

confidence: 94%

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A 2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.Keywords: adenosine; extracellular matrix; hyaluronic acid; remodeling; vascular Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death worldwide, and the World Health Organization predicts that it will become the third leading cause of death by 2030 (1). COPD is a heterogeneous disease characterized by airflow obstruction that is not fully reversible. Pathophysiological hallmarks of the disease include remodeling of the smallairway compartment, the loss of elastic recoil by emphysematous destruction of the parenchyma, inflammatory cell infiltration (2), and increased extracellular matrix (ECM) turnover (3). COPD is associated with a wide range of comorbidities, including ischemic heart disease, diabetes, skeletal muscle wasting, osteoporosis, and lung cancer (4). The development of pulmonary hypertension (PH) is a common and fatal complication in patients with COPD (5-7), and is strongly associated with decreased life expectancy (8).PH is a disorder of the pulmonary vasculature diagnosed by cardiac catheterization. PH is characterized by a mean pulmonary arterial pressure greater than or equal to 25 mm Hg that leads to right ventricular (RV) hypertrophy, followed by right-sided heart failure and death (9). Currently, treatment options are very limited for patients suffering from PH secondary to COPD (10, 11). Thus, to understand the mechanisms that lead to remodeling of the vasculature in COPD is important, with the hope of developing new treatment options for this fatal disorder.The pathogenesis of PH in COPD is a complex phenomenon characterized by extensive remodeling of the vasculature that results from an increased proliferation of pulmonary artery endothelial and smooth muscle cells, the muscularization of previously nonmuscular arteries, increased vascular tone, and the formation of complex vascular lesions (12). Factors involved in the development of PH in patients with COPD include ...

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“…Effects on RVP RVP is an indirect measure, but it represents a good estimate of the pulmonary artery pressure. 35 RVP was our primary endpoint, and as we hypothesized, the animals developed PH upon hypoxic exposure. RVP could be reduced by both Epo and, to a larger extent, sildenafil.…”

Section: Effects On Ventilationmentioning

confidence: 99%

Combination of Erythropoietin and Sildenafil Can Effectively Attenuate Hypoxia‐Induced Pulmonary Hypertension in Mice

et al. 2013

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Pulmonary hypertension (PH) is an incurable disease that often leads to right ventricular hypertrophy and right heart failure. This study investigated single versus combined therapy with sildenafil and erythropoietin on hypoxia-induced pulmonary hypertension in mice. Mice were randomized into 5 groups and exposed to either hypoxia (10% oxygen) or normoxia for a total of 5 weeks. Hypoxic mice were treated with saline solution, erythropoietin (500 IU/kg 3 times weekly), sildenafil (10 mg/kg daily), or a combination of the two drugs for the last 2 weeks of hypoxic exposure. We measured right ventricular pressures using right heart catheterization, and the ventilatory response to hypoxia was recorded via whole-body plethysmography. Histological analyses were performed to elucidate changes in pulmonary morphology and appearance of right heart hypertrophy. Plasma levels of cardiotrophin-1 and atrial natriuretic peptide were quantified. Treatment with either erythropoietin or sildenafil alone lowered the hypoxia-induced increase of pulmonary pressure and reduced pulmonary edema formation, pulmonary vascular remodeling, and right ventricular hypertrophy. Notably, the combination of the two drugs had the most prominent effect. Changes in cardiotrophin-1 and atrial natriuretic protein levels confirmed these observations. The combination treatment with erythropoietin and sildenafil demonstrated an attenuation of the development of hypoxia-induced PH in mice that was superior to that observed for either drug when given alone.

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A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects

Cited by 176 publications

References 125 publications

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Combination of Erythropoietin and Sildenafil Can Effectively Attenuate Hypoxia‐Induced Pulmonary Hypertension in Mice

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