Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia

Weißmann, Norbert; Manz, D; Buchspies, D.; Keller, Stephan Sylvest; Mehling, Tanja; Voswinckel, Robert; Quanz, Karin; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Fink, Ludger; Seeger, Werner; Gassmann, Max; Grimminger, Friedrich

doi:10.1160/th05-02-0104

Cited by 31 publications

(13 citation statements)

References 37 publications

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“…In hypoxic pulmonary hypertensive rats, right ventricular/body weight ratio and RVPs were not altered by EPO treatment, while pulmonary vascular remodelling ameliorated [6]. In mice with increased EPO production, pulmonary vasoconstrictor responses in isolated perfused lungs were decreased, as was pulmonary vascular remodelling, after a prolonged period of exposure to hypoxia [7,16]. Thus, investigations in different animal models for pulmonary hypertension strongly indicate that EPO beneficially affects pulmonary vascular remodelling, without changing haemodynamics or right ventricular hypertrophy.…”

Section: Discussionmentioning

confidence: 96%

“…EPO administration in the hypoxic rat model for pulmonary hypertension reduces pulmonary vascular remodelling, without effects on right ventricular hypertrophy or pulmonary pressures [6]. Furthermore, transgenic mice with increased EPO production appeared to be less sensitive to the development of hypoxic pulmonary hypertension [7]. In a recent study, mice lacking the EPO receptor had an accelerated development of pulmonary hypertension under hypoxic conditions, with more pronounced pulmonary vascular remodelling [8].…”

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confidence: 99%

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Effects of erythropoietin on advanced pulmonary vascular remodelling

Albada

Sarvaas²,

Koster³

et al. 2008

European Respiratory Journal

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Erythropoietin (EPO) mobilises endothelial progenitor cells and promotes neovascularisation in heart failure. The present authors studied the effects of EPO on pulmonary vascular and cardiac remodelling in a model for flow-associated pulmonary arterial hypertension (PAH).PAH was induced in adult male Wistar rats by the injection of monocrotaline combined with an abdominal aortocaval shunt 1 week later (PAH or experimental group). Immediately afterwards, rats were randomised into those who received treatment with EPO (PAH+EPO group) and controls. Pulmonary and systemic haemodynamics, and right ventricular and pulmonary vascular remodelling were evaluated 3 weeks later.Vascular occlusion of the intra-acinar pulmonary vessels (13.4¡0.7 versus 16.7¡1.3% in PAH+EPO and PAH, respectively) and medial wall thickness of the pre-acinar arteries (wall-tolumen ratio 0.13¡0.01 versus 0.17¡0.01 in PAH+EPO and PAH, respectively) decreased after treatment with EPO. Moreover, right ventricular capillary density was increased by therapy (2,322¡61 versus 2,100¡63 capillaries?mm -2 in PAH+EPO and PAH, respectively). Increased mean pulmonary arterial pressure and decreased right ventricular contractility in the model were not altered by EPO treatment. In this rat model of flow-associated pulmonary arterial hypertension, erythropoietin treatment beneficially affected pulmonary vascular and cardiac remodelling. These histopathological effects were not accompanied by significantly improved haemodynamics.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Effects of erythropoietin on advanced pulmonary vascular remodelling

Albada

Sarvaas²,

Koster³

et al. 2008

European Respiratory Journal

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“…The animals were exposed to 3 weeks of either hypoxia (10% oxygen) or normoxia (room air), after which the animals received the different drugs for additional 2 weeks under the same environmental conditions. This hypoxic mouse model for PH is well established, has been described by several groups, 20,[24][25][26] and is known to result in PH after 3 weeks of hypoxic exposure. The normobaric hypoxic chamber was opened for 1 hour once per week to replace bedding, water bottles, and chow.…”

Section: Materials and Methods Animals And Hypoxic Treatmentmentioning

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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“…The animals were exposed to chronic hypoxia (10% O 2) in a ventilated chamber, as described previously (43,44). The level of hypoxia was held constant by an autoregulatory control unit (model 4010, O 2 controller; Labotect; Göttingen, Germany) supplying either nitrogen or oxygen.…”

Section: Methodsmentioning

confidence: 99%

The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice

Weißmann

Hackemack

Dahal

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Schermuly RT. The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 297: L658 -L665, 2009. First published July 17, 2009 doi:10.1152/ajplung.00189.2009.-Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dosedependently inhibited the pressor response of acute hypoxia. This dose-response curve was shifted leftward when the effects of HMR1766 were investigated in isolated lungs from chronic hypoxic animals for 21 days at 10% oxygen. Mice exposed for 21 or 35 days to chronic hypoxia developed PH, right heart hypertrophy, and pulmonary vascular remodeling. Treatment with HMR1766 (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH. vascular remodeling; telemetry PULMONARY HYPERTENSION (PH) is a disabling disease characterized by vascular remodeling and right ventricular hypertrophy. Hypoxia is considered a major factor in the pathogenesis of PH, e.g., PH associated with high altitude and with chronic restrictive or obstructive lung diseases. Whereas acute hypoxia causes a selective pulmonary arteriolar vasoconstriction and increases pulmonary arterial pressure, the exposure to chronic hypoxia induces structural and functional changes of the pulmonary vasculature (15,18). In the context of chronic hypoxia, an imbalance in vasodilatory [e.g., prostacyclin, nitric oxide (NO)] and vasoconstrictive (e.g., thromboxane, endothelin) molecules has been implicated in pulmonary arterial vasoconstriction and chronic vascular remodeling.One potent vasodilator is NO, which is synthesized by NO synthases and is considered to be a key player in regulating pulmonary vascular tone. The downstream effector of NO is the soluble guanylate cyclase (sGC), which synthesizes the second messenger guanosine 3Ј,5Ј-cyclic monophosphate (cGMP) in smooth muscle cells, thus causing vasorelaxation.

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Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia

Cited by 31 publications

References 37 publications

Effects of erythropoietin on advanced pulmonary vascular remodelling

Effects of erythropoietin on advanced pulmonary vascular remodelling

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

The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice

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