Reversal of pulmonary vascular remodeling in pulmonary hypertensive rats

Sluiter, Ilona; Heijst, Arno van; Haasdijk, Remco; Kempen, Marjon Buscop-van; Munck, Anne Boerema-de; Tibboel, Dick; Rottier, Robbert J.

doi:10.1016/j.yexmp.2012.03.010

Cited by 20 publications

(19 citation statements)

References 57 publications

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“…Thus, we speculate that our treatment duration may not be optimal to reverse the disease and that longer exposure times may be required. In support of this it has been shown that the complete reduction in medial thickness induced by the relatively mild stimulus of chronic hypoxia takes 6 weeks after the animals are returned to normoxia [81]. Therefore, in conclusion, we speculate that the administration of bosentan for a longer period could provide greater beneficial results, perhaps leading to the reversal of the PH phenotype.…”

Section: Discussionsupporting

confidence: 79%

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Rafikova

Rafikov

Kumar

et al. 2013

Free Radical Biology and Medicine

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Pulmonary arterial hypertension (PH) is a fatal disease marked by excessive pulmonary vascular cell proliferation. Patients with idiopathic PH express endothelin-1 (ET-1) at high levels in their lungs. As the activation of both types of ET-1 receptor (ETA and ETB) leads to increased generation of superoxide and hydrogen peroxide, this may contribute to the severe oxidative stress found in PH patients. As a number of pathways may induce oxidative stress, the particular role of ET-1 remains unclear. The aim of this study was to determine whether inhibition of ET-1 signaling could reduce pulmonary oxidative stress and attenuate the progression of disease in rats with occlusive-angioproliferative PH induced by a single dose of SU5416 (200 mg/kg) and subsequent exposure to hypoxia for 21 days. Using this regimen, animals developed severe PH as evidenced by a progressive increase in right-ventricle (RV) peak systolic pressure (RVPSP), severe RV hypertrophy, and pulmonary endothelial and smooth muscle cell proliferation, resulting in plexiform vasculopathy. PH rats also had increased oxidative stress, correlating with endothelial nitric oxide synthase uncoupling and NADPH oxidase activation, leading to enhanced protein nitration and increases in markers of vascular remodeling. Treatment with the combined ET receptor antagonist bosentan (250 mg/kg/day; day 10 to 21) prevented further increase in RVPSP and RV hypertrophy, decreased ETA/ETB protein levels, reduced oxidative stress and protein nitration, and resulted in marked attenuation of pulmonary vascular cell proliferation. We conclude that inhibition of ET-1 signaling significantly attenuates the oxidative and nitrosative stress associated with PH and prevents its progression.

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Section: Discussionsupporting

confidence: 79%

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Rafikova

Rafikov

Kumar

et al. 2013

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…4,9, 17 Additionally, hypoxia-induced medial hypertrophy is also considered to be reversible on restoration of normoxia. 18, 19 In our study, medial hypertrophy was reversible in most patients, but was not fully achieved in patients aged >6 months at PAB. This finding is different from that in the previous report, 4 which showed reverse remodeling of medial hypertrophy in patients who underwent PAB at over 6 months of age.…”

Section: Histologic and Histomorphometric Changes Between The 2 Biopsmentioning

confidence: 47%

Evidence of Pulmonary Vascular Reverse Remodeling After Pulmonary Artery Banding Performed in Early Infancy in Patients With Congenital Heart Defects

Masaki

Saiki

Endo

et al. 2018

Circ J

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for PAB from the view point of reversibility of pulmonary vascular lesions has not been fully described. The aim of this study was to evaluate pulmonary vascular reverse remodeling after PAB using serial lung biopsy specimens and to draw conclusions on the optimal timing for PAB in terms of pulmonary vascular reverse remodeling. Methods SubjectsNumerous lung biopsy and autopsy specimens have been collected from multiple centers in Japan for diagnosing pulmonary vascular disease (PVD). Out of a total of 1,293 lung biopsy and autopsy specimens collected at our institution between January 2001 and December 2015, 41 patients who had undergone lung biopsies before and after PAB were identified. Of these, 34 patients had a ventricular septal defect (VSD) or atrioventricular septal defect (AVSD) and they were selected as the cohort for the present study. The other 7 patients with complex cardiac anomalies, such as single ventricular morphology, were excluded to evaluate P ulmonary artery banding (PAB) was introduced in 1952 as a palliative surgical procedure for the treatment of congenital heart diseases with excessive pulmonary blood flow. 1 The technique has been extensively used as part of a staged approach for the surgical correction of congenital heart defects. The procedure is also used for patients who are unable to withstand primary corrective surgery for congenital heart defects because of associated lung pathology and anatomical complexity. PAB is aimed at hemodynamic restoration and reduction of excessive blood flow and pressure in the pulmonary circulation, 2 thus protecting the pulmonary vasculature from irreversible changes that may otherwise lead to severe pulmonary arteriopathy. 3 Reverse remodeling of pulmonary arteriopathy following PAB was once reported by Wagenvoort et al more than 30 years ago; 4 medial hypertrophy and intimal lesions appeared to improve with this treatment. To the best of our knowledge, that report is the only one describing the reversibility of pulmonary artery lesions; however, histomorphometric evidence of such reversibility has not yet been well established. Additionally, the optimal timing Background: Histomorphometric evidence of the effect of pulmonary artery banding (PAB) in infancy on pulmonary vascular reverse remodeling has not been fully described.

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“…However, arteries with dilatation lesions that show dilated segments with degenerative changes in SMCs did not develop plexiform lesions (127)(128)(129). Furthermore, the hypoxia-induced PH is reversible upon removal of hypoxic condition (17,118). Unlike the MCT model that is associated with a progressive loss of caveolin-1 and subsequent reduction in the expression of eNOS, there is no loss of endothelial caveolin-1 or eNOS expression in the hypoxia model of PH (87).…”

Section: Perturbation Of Ec Membranementioning

confidence: 99%

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

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Reversal of pulmonary vascular remodeling in pulmonary hypertensive rats

Cited by 20 publications

References 57 publications

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Evidence of Pulmonary Vascular Reverse Remodeling After Pulmonary Artery Banding Performed in Early Infancy in Patients With Congenital Heart Defects

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

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