Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease

Geiger, R.; Berger, Rudolphus; Hess, J; Bogers, A. J. J. C.; Sharma, Hari Shanker; Mooi, Walter

doi:10.1002/(sici)1096-9896(200006)191:2<202::aid-path608>3.3.co;2-4

Cited by 28 publications

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“…VEGF and its receptors play a key role during embryonic vasculogenesis and also during normal and pathological angiogenesis. Increased expression of VEGF and its receptor VEGF-R2 has been reported in plexiform lesions in the lungs of patients with idiopathic PAH and PAH secondary to CHD (38,46,127). Interestingly, similar to human plexiform lesions, increased expression of VEGF and VEGF-R2 has been reported in the complex lesions found in the VEGF-R2 blocker ϩ hypoxia model of severe PH.…”

Section: Caveolin-1 and Plexiform Lesionsmentioning

confidence: 74%

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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Section: Caveolin-1 and Plexiform Lesionsmentioning

confidence: 74%

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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“…Increased VEGF expression has been demonstrated specifically in the plexiform lesions of patients with PAH [28,29]. This may suggest a role for VEGF in the pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 88%

Effects of erythropoietin on advanced pulmonary vascular remodelling

Albada

Sarvaas²,

Koster³

et al. 2007

Eur Respir J

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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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“…These vascular lesions are characterised by vascular smooth muscle and endothelial cell proliferation. In contrast, in patients with congenital heart defects and isolated increased pulmonary artery pressure (PAP), these lesions almost never develop [1,2]. The current authors hypothesise that, in congenital heart defects, increased pulmonary blood flow, in addition to increased pressure, is a pre-requisite for the development of the hallmark lesions of advanced pulmonary arterial hypertension.…”

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confidence: 90%

The role of increased pulmonary blood flow in pulmonary arterial hypertension

Albada¹,

Schoemaker²,

Kemna³

et al. 2005

Eur Respir J

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Chronic increased pulmonary blood flow is considered a pre-requisite for the induction of advanced vascular lesions in pulmonary arterial hypertension in congenital heart defects. The aim of the present study was to characterise the effects of increased pulmonary flow induced by an aortocaval shunt in the monocrotaline rat model for pulmonary hypertension in terms of survival, haemodynamics, pathology and histology.Male Wistar rats were injected with monocrotaline followed by the creation of an abdominal aortocaval shunt. Animals were sacrificed when displaying symptoms of weight loss or dyspnoea, 4-5 weeks after the creation of the shunt.Echocardiography identified increased ventricular dimensions in shunted rats and right ventricular hypertrophy in monocrotaline-treated rats. At similar pulmonary artery pressures, shunted monocrotaline rats displayed higher morbidity and mortality, increased pulmonary-tosystemic artery pressure ratios and increased right ventricular hypertrophy compared with nonshunted monocrotaline rats. Histological assessment demonstrated increased number and diameter of pre-acinar pulmonary arteries. Intra-acinar vessel remodelling and occlusion occurred to a similar extent in shunted and nonshunted monocrotaline rats.In conclusion, increased pulmonary blood flow in monocrotaline-induced pulmonary hypertension is associated with increased morbidity, mortality, and unfavourable haemodynamic and cardiac effects. These effects could be attributed to more pronounced right heart failure rather than to altered intra-acinar pulmonary vessel remodelling. KEYWORDS: Animal model, congenital heart disease, plexogenic arteriopathy, pulmonary arterial hypertension, pulmonary vascular histopathology, right heart failure P atients with congenital heart disease associated with systemic-to-pulmonary shunts, increasing both pulmonary blood flow and pressure, develop characteristic pulmonary vascular lesions as concentric-laminar intimal fibrosis and plexiform lesions. These vascular lesions are characterised by vascular smooth muscle and endothelial cell proliferation. In contrast, in patients with congenital heart defects and isolated increased pulmonary artery pressure (PAP), these lesions almost never develop [1,2]. The current authors hypothesise that, in congenital heart defects, increased pulmonary blood flow, in addition to increased pressure, is a pre-requisite for the development of the hallmark lesions of advanced pulmonary arterial hypertension.Animal models with an isolated increase in PAP, e.g. induced by the toxic alkaloid monocrotaline, show pulmonary vascular remodelling, but fail to display the more advanced lesions as described previously [3-5].The role of increased pulmonary blood flow has been explored in animal models [6]. In rat models with isolated increased flow [7,8], a moderate increase in pulmonary pressure and medial hypertrophy has been observed, but only after a prolonged period of exposure.When the additional effect of flow was explored in existing rat models for pul...

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Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease

Cited by 28 publications

References 0 publications

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

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

Effects of erythropoietin on advanced pulmonary vascular remodelling

The role of increased pulmonary blood flow in pulmonary arterial hypertension

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