Effects of erythropoietin on advanced pulmonary vascular remodelling

Albada, Mirjam E. van; Sarvaas, Gideon J. du Marchie; Koster, J.; Houwertjes, M. C.; Berger, Rudolphus; Schoemaker, Regien G.

doi:10.1183/09031936.00035607

Cited by 21 publications

(22 citation statements)

References 51 publications

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“…Global changes in vascular bed increase the pulmonary vascular resistance and induce elevated RVP and PAP, features that are known as pulmonary hypertension 29. Indeed lung irradiation was found to induce pulmonary hypertension by showing an irradiated-volume dependent increase in all components of RVP and PAP, despite the decreasing dose (figure 5A).…”

Section: Resultsmentioning

confidence: 97%

Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Ghobadi

Bartelds

Veen

et al. 2011

Thorax

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Background Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. Methods Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. Results Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. Conclusions The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.

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Section: Resultsmentioning

confidence: 97%

Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Ghobadi

Bartelds

Veen

et al. 2011

Thorax

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“…Other groups have reported, for instance, a blunted response to U46619 in isolated perfused lungs of tg6 animals 39 as well as in Epo-treated rats. 40 In the monocrotaline rat model of PH, both negative 22 and positive 41 effects of Epo have been reported, whereas in Hilltop and Madison rats exposed to hypoxia, no effects were observed. 23 Finally, an Epo receptor knockout model revealed a higher pulmonary vascular response after hypoxic exposure.…”

Section: Effects On Ventilationmentioning

confidence: 99%

“…19 In addition, protective effects of Epo in hypoxia-induced PH have been ficient in the Epo receptor, 21 but not in two rat models. 22,23 In this study, we tested the hypothesis that combined treatment with the vasodilator sildenafil and recombinant human Epo may have superior effects on hypoxia-induced PH, as compared to treatment with each drug alone. The primary endpoint of the study was right ventricular pressure (RVP), and secondary endpoints were morphology of the right heart ventricle and remodeling of the pulmonary arterial vessels.…”

Section: Introductionmentioning

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 phosphorylation of EPOR generates a variety of signaling molecules, such as PI3K (10), which inhibit apoptosis, induce cell proliferation, and promote p-eNOS (1,43). In vivo, EPO treatment beneficially reduced the severity of pulmonary vascular and cardiac remodeling of the subjects with experimental PH (31,44). In endothelial cells, both EPO and hypoxia increased EPOR and eNOS expression (3).…”

mentioning

confidence: 95%

Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system

Kuriyama

Morio

Toba

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser(1177) and p-Akt at Ser(473) expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system.

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Effects of erythropoietin on advanced pulmonary vascular remodelling

Cited by 21 publications

References 51 publications

Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

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

Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system

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