Pulmonary Hypertension: Endothelial Cell Function

Mathew, Rajamma

doi:10.5772/26198

Cited by 5 publications

(6 citation statements)

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“…BMPR2 gene therapy fails to inhibit MCT-induced PH; however, administration of GDF2 (growth differentiation factor 2, also known as BMP9) was shown to have preventive and reversal effect on experimental PH [9,10]. BMPR2 is predominantly expressed in endothelial cells and a part of it co-localizes with CAV1 [11], and the loss of BMPR2 increases the susceptibility to DNA damage [12]. The increased expression of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) that induces lysosomal and proteosomal degradation of BMPR2 has been shown to occur in patients with PAH, as well as in hypoxia and MCT-induced PH.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, Cav1 knockout mice develop PH which can be reversed by reconstituting endothelial Cav1 [16,17]. Extensive loss of endothelial CAV1 accompanied by enhanced expression of CAV1 in vascular smooth muscle cells (VSMC) has been reported in IPAH, HPAH, in PAH associated with congenital heart defect and drug toxicity [11,[18][19][20] and in infants with bronchopulmonary dysplasia and evidence of inflammation [19]. Furthermore, pulmonary artery smooth muscle cells isolated from patients with PH revealed enhanced expression of CAV1, increased capacitative Ca 2+ entry and increased DNA synthesis which could be blocked by…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Mathew

Huang

Iacobaş

et al. 2019

Preprint

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Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), lung histology and transcriptomes of six weeks old male rats with PH induced by: 1) hypoxia (HO), 2) administration of monocrotaline (CM) or 3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations and also neointimal lesions and obliteration of lumen in small arteries. We found that the PH increased the expression of caveolin1, matrix metallopeptidase 2 and numerous inflammatory and cell proliferation genes. The cell-cycle, vascular smooth muscle contraction and the oxidative phosphorylation pathways, as well as their interplay were largely perturbed. Our results also suggest that the up-regulated Rhoa (ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed especially in HM group, indicate metabolic shift towards aerobic glycolysis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Mathew

Huang

Iacobaş

et al. 2019

Preprint

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“…In susceptible individuals, augmentation of pulmonary arterial pressure results in PH and ET-1 secretion above the upper physiological limits. ET-1 migrates to muscle cells, where it enhances Ca 2+ -calmodulin way and protein kinases; muscle contraction ensues and the remodeling process takes place due to a complex molecular framework (16,17). Although the mechanism of action of ET-1 in the pulmonary Para declarar diferencias estadísticas, el nivel de significancia tuvo que ser p<0.01.…”

Section: Discussionmentioning

confidence: 99%

“…When this compensatory mechanism is sustained as to increase pulmonary arterial blood flow and overpass physiological levels, PH occurs (4,5). Also, nitric oxide synthase sequester can develop, thus inhibiting vasodilatation due to decrease in nitric oxide (6). This endothelial dysfunction, vasoconstrictors predominate and vascular remodeling ensues, which entails thickening of the middle muscle and the adventitia layers in arterioles (5).…”

Section: Introductionmentioning

confidence: 99%

“…Cuando este mecanismo compensatorio se mantiene para incrementar el flujo de sangre arterial y sobrepasa los niveles fisiológicos, sobreviene la HP (4,5). Así mismo, puede cocurrir el secuestro de la sintasa de óxido nítrico y así se inhibiría la vasodilatación por la disminución de óxido nítrico (6). En esta disfunción endotelial predominan los vasoconstrictores y ocurre una remodelación vascular, que incluye el engrosamiento de la media muscular y de la adventicia en arteriolas (5).…”

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Expresión de Endotelina-1 en pollos con hipertensión arterial pulmonar por hipoxia hipobárica

Hernández

2017

Rev MVZ Córdoba

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Objective. To determine the effect of hypobaric hypoxia exposition in pulmonary arterioles expression of endothelin-1 (ET-1). Materials and methods. Two groups of commercial broiler chickens were used: one of them were raised at 2638 (hypobaric hypoxia) and the other one at 300 m (relative normoxia) above sea level. Incidence of pulmonary hypertension (PH) was evaluated by calculating the cardiac mass index values and ET-1 protein expression was established in pulmonary arterioles by immunohistochemistry and morphometry. Results. ET-1 expression was higher in arterioles of animals exposed to hypoxia as compared to the low altitude exposed broilers (p<0.01). Arterioles from pulmonary hypertensive chickens (PHC) showed ET-1 higher expression than arterioles from healthy chickens (non-hypertensive, NHC) at low altitude, those exposed to hypobaric hypoxia (p<0.01). 53% of chickens subjected to altitude conditions developed pulmonary hypertension. Under normoxia, no chickens developed that pathology. Conclusions. Quantitative characteristics and sites of ET-1 expression in the lungs are important in the understanding of PH pathogenesis in broilers and the adapting mechanisms to hypobaric hypoxia, as to design new pharmacological approaches. This is a first approach which accounts for the abovementioned features in broilers subjected to natural conditions of normoxia and hypobaric hypoxia.Keywords: Arterioles, endothelin-1, pulmonary hypertension, morphometry, immunohistochemistry (Source: CAB). RESUMENObjetivo. Determinar el efecto de la exposición a hipoxia hipobárica sobre la expresión de Endotelina-1 en arteriolash pulmonares. Material y métodos. Se utilizaron 2 grupos de pollos de engorde de una estirpe comercial: uno de ellos criados a 2638 y el otro, a 300 m de altitud. La incidencia de HAP se evaluó según los valores del índice de masa cardiaca y se compararon los niveles de expresión de la proteína ET-1 en arteriolas pulmonares de pollos de engorde sanos y enfermos por HAP mediante inmunohistoquímica y morfometría. Resultados. La expresión de la proteína ET-1 fue mayor en las arteriolas de los pollos expuestos a hipoxia hipobárica que en los criados bajo condiciones de normoxia DOI: doi.org/10.21897/rmvz.1032 5952 REVISTA MVZ CÓRDOBA • Volumen 22(2) Mayo -Agosto 2017 relativa (p<0.01). Los animales enfermos por HAP presentaron mayor expresión de la proteína ET-1 en las arteriolas pulmonares que los animales sanos ubicados en las dos altitudes (p<0.01). 53% de los animales desarrollaron hipertensión pulmonar y ninguno de los mantenidos en normoxia lo hicieron. Conclusiones. El conocimiento de las características cuantitativas y lo sitios de expresión de la ET-1 son elementos importantes para entender aún más la patogenia de la HAP y el diseño de fármacos para su control. Este estudio constituye la primera aproximación cuantitativa relacionada con la expresión de ET-1 en pollos de engorde con HAP de origen hipóxico no inducida.

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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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Pulmonary Hypertension: Endothelial Cell Function

Cited by 5 publications

References 109 publications

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Expresión de Endotelina-1 en pollos con hipertensión arterial pulmonar por hipoxia hipobárica

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

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