Sildenafil improves vascular endothelial function in patients with cystic fibrosis

Rodriguez‐Miguelez, Paula; Lee, Nichole; Tucker, Matthew A.; Csányi, Gábor; McKie, Kathleen T.; Forseen, Caralee; Harris, Ryan A.

doi:10.1152/ajpheart.00301.2018

Cited by 17 publications

(16 citation statements)

References 55 publications

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“…In vitro treatment of human umbilical vein endothelial cells (HUVEC) with CFTR inhibitor suppressed insulin-induced NO generation, by inhibiting eNOS and AKT activation/phosphorylation [ 37 ]. Besides, ECs exposed to plasma from patients with CF treated with sildenafil demonstrated increased protein expression of phosphorylated and total eNOS compared to placebo-treated patients [ 35 ]. Overall, these findings point to decreased endothelial NO in CF ( Fig.…”

Section: Vascular Tonementioning

confidence: 81%

“…In the same study, a positive relationship between microvascular function and lung function was found suggesting that disease severity may contribute, at least in part, to microvascular dysfunction [ 34 ]. In follow-up studies, the same group demonstrated that four weeks treatment with sildenafil (an inhibitor of phosphodiesterase 5 that enhances NO metabolism) [ 35 ] and tetrahydrobiopterin (BH 4 , a determinant of NO bioavailability) [ 36 ] increased FMD in patients with CF. In vitro treatment of human umbilical vein endothelial cells (HUVEC) with CFTR inhibitor suppressed insulin-induced NO generation, by inhibiting eNOS and AKT activation/phosphorylation [ 37 ].…”

Section: Vascular Tonementioning

confidence: 85%

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The role of endothelial cells in cystic fibrosis

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Treps

Carmeliet

et al. 2019

Journal of Cystic Fibrosis

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Section: Vascular Tonementioning

confidence: 81%

Section: Vascular Tonementioning

confidence: 85%

The role of endothelial cells in cystic fibrosis

Declercq

Treps

Carmeliet

et al. 2019

Journal of Cystic Fibrosis

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“…Recently, many kinds of small molecules were synthesized to enhance angiogenesis. Sildenafil, a phosphodiesterase type 5 inhibitor, not only enhances nitric oxide metabolism but has been shown to improve vascular endothelial function [177]. Lithium was also shown to have a concentration-dependent effect on early vascular development in the chick embryo area vasculosa [178].…”

Section: Small Moleculers-based Approaches For Vascular Networkmentioning

confidence: 99%

3D Bioprinting for Vascularized Tissue-Engineered Bone Fabrication

et al. 2020

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Vascularization in bone tissues is essential for the distribution of nutrients and oxygen, as well as the removal of waste products. Fabrication of tissue-engineered bone constructs with functional vascular networks has great potential for biomimicking nature bone tissue in vitro and enhancing bone regeneration in vivo. Over the past decades, many approaches have been applied to fabricate biomimetic vascularized tissue-engineered bone constructs. However, traditional tissue-engineered methods based on seeding cells into scaffolds are unable to control the spatial architecture and the encapsulated cell distribution precisely, which posed a significant challenge in constructing complex vascularized bone tissues with precise biomimetic properties. In recent years, as a pioneering technology, three-dimensional (3D) bioprinting technology has been applied to fabricate multiscale, biomimetic, multi-cellular tissues with a highly complex tissue microenvironment through layer-by-layer printing. This review discussed the application of 3D bioprinting technology in the vascularized tissue-engineered bone fabrication, where the current status and unique challenges were critically reviewed. Furthermore, the mechanisms of vascular formation, the process of 3D bioprinting, and the current development of bioink properties were also discussed.

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“…In vivo endothelial cells are constantly exposed to shear stress resulting in the activation of several mechanoresponsive networks, which increase the expression of genes that regulate inflammation, such as the vascular cell adhesion molecule (Zhou et al, 2014) and bioavailability of the vasodilator nitric oxide (NO), such as endothelial NO synthase (eNOS) (Chistiakov et al, 2017). In CF, defective flowmediated dilation (FMD) of the brachial artery suggests NO bioavailability is reduced in response to shear stress (Poore et al, 2013), and improved by agents that increase NO availability (Rodriguez-Miguelez et al, 2018). This notion is further supported by the observation that acute supplementation with 20 mg/kg of oral tetrahydrobiopterin (an essential cofactor for eNOS activity) significantly improved FMD, through reduced superoxide production and increased NO, which is indicative of improved eNOS coupling in people with CF (Jeong et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

CFTR limits F‐actin formation and promotes morphological alignment with flow in human lung microvascular endothelial cells

et al. 2021

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Micro-and macrovascular endothelial dysfunction in response to shear stress has been observed in cystic fibrosis (CF), and has been associated with inflammation and oxidative stress. We tested the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) regulates endothelial actin cytoskeleton dynamics and cellular alignment in response to flow. Human lung microvascular endothelial cells (HLMVEC) were cultured with either the CFTR inhibitor GlyH-101 (20 µM) or CFTRinh-172 (20 µM), tumor necrosis factor (TNF)-α (10 ng/ml) or a vehicle control (0.1% dimethyl sulfoxide) during 24 and 48 h of exposure to shear stress (11.1 dynes/cm 2 ) or under static control conditions. Cellular morphology and filamentous actin (F-actin) were assessed using immunocytochemistry.[Nitrite] and endothelin-1 ([ET-1]) were determined in cell culture supernatant by ozone-based chemiluminescence and ELISA, respectively. Treatment of HLMVECs with both CFTR inhibitors prevented alignment of HLMVEC in the direction of flow after 24 and 48 h of shear stress, compared to vehicle control (both p < 0.05). Treatment with TNF-α significantly increased total F-actin after 24 h versus control (p < 0.05), an effect that was independent of shear stress. GlyH-101 significantly increased F-actin after 24 h of shear stress versus control (p < 0.05), with a significant (p < 0.05) reduction in cortical Factin under both static and flow conditions. Shear stress decreased [ET-1] after 24 h (p < 0.05) and increased [nitrite] after 48 h (p < 0.05), but neither [nitrite] nor [ET-1] was affected by GlyH-101 (p > 0.05). CFTR appears to limit cytosolic actin polymerization, while maintaining a cortical rim actin distribution that is important for maintaining barrier integrity and promoting alignment with flow, without effects on endothelial nitrite or ET-1 production.

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Sildenafil improves vascular endothelial function in patients with cystic fibrosis

Abstract: These data suggest that four weeks of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation.

Cited by 17 publications

References 55 publications

The role of endothelial cells in cystic fibrosis

The role of endothelial cells in cystic fibrosis

3D Bioprinting for Vascularized Tissue-Engineered Bone Fabrication

CFTR limits F‐actin formation and promotes morphological alignment with flow in human lung microvascular endothelial cells

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