Pulmonary Vascular Remodeling in Pulmonary Hypertension

Jia, Zhuangzhuang; Wang, Shuai; Yan, Haifeng; Cao, Yawen; Zhang, Xuan; Wang, Lin; Zhang, Zeyu; Lin, Shanshan; Wang, Xianliang; Mao, Jingyuan

doi:10.3390/jpm13020366

Cited by 23 publications

(10 citation statements)

References 154 publications

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“…Our study for the first time presents compelling evidence that Jag2 is activated during the development of PH.Furthermore, our findings reveal a potentially promising new therapeutic strategy for PH, as we demonstrate that Jag2 inhibition can reverse the pathological antiapoptotic and proliferative phenotype of PASMCs. The main protagonist in PH is pulmonary vascular remodeling, characterized by a thickening of the vascular intima and media, which is widely believed to arise through hypertrophy, proliferation, migration, and extracellular matrix deposition of various cell types including endothelial cells, smooth muscle cells, fibroblasts, inflammatory cells, and platelets [21].Previous studies have demonstrated a constant level of the Notch ICD in the small pulmonary arteries of patients with PH. Additionally, cleavage of the Notch receptor induces proliferation of…”

Section: Discussionmentioning

confidence: 99%

Jagged 2 inhibition attenuates hypoxia-induced mitochondrial damage and pulmonary hypertension through Sirtuin 1 signaling

Liu,

Pan,

et al. 2024

PLoS ONE

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Notch pathway has played a significant role in the pathophysiology of pulmonary hypertension (PH). However, the role of Jagged 2 (Jag2), one ligand of Notch, remains to be elucidated.Therefore, determining the contribution of Jag2 to PH and its impact on pulmonary artery smooth muscle cells (PASMCs) was the aim of this investigation. Adeno-associated virus-mediated Jag2 inhibition was used to explore the role of Jag2 in peripheral pulmonary vascular remodeling assessed in a rat model of chronic hypoxia (10% O2, 4 weeks) induced pulmonary hypertension. In vitro, the effect of Jag2 silencing on hypoxia (1% O2, 24h) induced rat PASMCs was determined. Group differences were assessed using a 2-sided unpaired Student’s t-test for two groups and one-way ANOVA for multiple groups. Jag2 upregulation was first confirmed in rats with sustained hypoxia-induced PH using publicly available gene expression data, experimental PH rat models and hypoxia induced rat PASMCs. Jag2 deficiency decreased oxidative stress injury, peripheral pulmonary vascular remodeling (0.276±0.020 vs. 0.451±0.033 μm, P<0.001, <50μm), and right ventricular systolic pressure (36.8±3.033 vs. 51.8±4.245 mmHg, P<0.001) in the chronic hypoxia-induced rat model of PH. Moreover, Jag2 knockdown decreased proliferation (1.227±0.051 vs. 1.45±0.07, P = 0.012), increased apoptosis (16.733%±0.724% vs. 6.56%±0.668%, P<0.001), and suppressed mitochondrial injury in hypoxia–treated rat PASMCs. Jag2 inhibition restored the activity of the Nrf2/HO-1 pathway, which was abolished by Sirtuin 1 deficiency. These findings show that Jag2 is essential for modulating pulmonary vascular dysfunction and accelerating PH, and that inhibition of Jag2 expression suppresses the progression and development of PH.

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Section: Discussionmentioning

confidence: 99%

Jagged 2 inhibition attenuates hypoxia-induced mitochondrial damage and pulmonary hypertension through Sirtuin 1 signaling

Liu,

Pan,

et al. 2024

PLoS ONE

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“…As an important transcriptional regulator involved in the modulating angiogenesis, enhancement of vascular permeability, and vascular remodeling, the HIF-1α signaling pathway increases connective tissue expression in endothelial cells under hypoxic stimulation [65][66][67]. VEGF not only increases vascular permeability but also promotes the proliferation and differentiation of vascular smooth muscle cells, thereby promoting neovascularization [68][69][70]. Together with the experimental results, the structure of the lungs determines whether yaks can adapt to the hypoxic environment of the plateau [51,71,72].…”

Section: Discussionmentioning

confidence: 99%

Study of Transcriptomic Analysis of Yak (Bos grunniens) and Cattle (Bos taurus) Pulmonary Artery Smooth Muscle Cells under Oxygen Concentration Gradients and Differences in Their Lung Histology and Expression of Pyruvate Dehydrogenase Kinase 1-Related Factors

Zhang,

Zhou,

Liang

et al. 2023

Animals

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The aim of this study was to investigate the molecular mechanisms by which hypoxia affects the biological behavior of yak PASMCs, the changes in the histological structure of yak and cattle lungs, and the relationships and regulatory roles that exist regarding the differences in the distribution and expression of PDK1 and its hypoxia−associated factors screened for their role in the adaptation of yak lungs to the plateau hypoxic environment. The results showed that, at the level of transcriptome sequencing, the molecular regulatory mechanisms of the HIF−1 signaling pathway, glucose metabolism pathway, and related factors (HK2/PGK1/ENO1/ENO3/ALDOC/ALDOA) may be closely related to the adaptation of yaks to the hypoxic environment of the plateau; at the tissue level, the presence of filled alveoli and semi−filled alveoli, thicker alveolar septa and basement membranes, a large number of erythrocytes, capillary distribution, and collagen fibers accounted for all levels of fine bronchioles in the lungs of yaks as compared to cattle. A higher percentage of goblet cells was found in the fine bronchioles of yaks, and PDK1, HIF−1α, and VEGF were predominantly distributed and expressed in the monolayers of ciliated columnar epithelium in the branches of the terminal fine bronchioles of yak and cattle lungs, with a small amount of it distributed in the alveolar septa; at the molecular level, the differences in PDK1 mRNA relative expression in the lungs of adult yaks and cattle were not significant (p > 0.05), the differences in HIF−1α and VEGF mRNA relative expression were significant (p < 0.05), and the expression of PDK1 and HIF−1α proteins in adult yaks was stronger than that in adult cattle. PDK1 and HIF−1α proteins were more strongly expressed in adult yaks than in adult cattle, and the difference was highly significant (p < 0.01); the relative expression of VEGF proteins was not significantly different between adult yaks and cattle (p > 0.05). The possible regulatory relationship between the above results and the adaptation of yak lungs to the plateau hypoxic environment paves the way for the regulatory mechanisms of PDK1, HIF−1α, and VEGF, and provides basic information for studying the mechanism of hypoxic adaptation of yaks in the plateau. At the same time, it provides a reference for human hypoxia adaptation and a target for the prevention and treatment of plateau diseases in humans and plateau animals.

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“…Pulmonary vascular remodeling is characterized by the medial thickening of the vessel wall, which reduces arterial inner diameter and increases vascular resistance. This process can result from changes in the intima, media, and adventitia with a key contribution of inflammatory cells [ 108 , 109 ]. Given the enhanced role of inflammation in PF, as compared with other causes of PH, the role of inflammatory mediators in pulmonary vascular remodeling may be enhanced in this setting.…”

Section: Sensory Nerves In Vascular Dysfunctionmentioning

confidence: 99%

Role of Sensory Nerves in Pulmonary Fibrosis

Norton

2024

IJMS

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Pulmonary fibrosis results from the deposition and proliferation of extracellular matrix components in the lungs. Despite being an airway disorder, pulmonary fibrosis also has notable effects on the pulmonary vasculature, with the development and severity of pulmonary hypertension tied closely to patient mortality. Furthermore, the anatomical proximity of blood vessels, the alveolar epithelium, lymphatic tissue, and airway spaces highlights the need to identify shared pathogenic mechanisms and pleiotropic signaling across various cell types. Sensory nerves and their transmitters have a variety of effects on the various cell types within the lungs; however, their effects on many cell types and functions during pulmonary fibrosis have not yet been investigated. This review highlights the importance of gaining a new understanding of sensory nerve function in the context of pulmonary fibrosis as a potential tool to limit airway and vascular dysfunction.

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Pulmonary Vascular Remodeling in Pulmonary Hypertension

Cited by 23 publications

References 154 publications

Jagged 2 inhibition attenuates hypoxia-induced mitochondrial damage and pulmonary hypertension through Sirtuin 1 signaling

Jagged 2 inhibition attenuates hypoxia-induced mitochondrial damage and pulmonary hypertension through Sirtuin 1 signaling

Study of Transcriptomic Analysis of Yak (Bos grunniens) and Cattle (Bos taurus) Pulmonary Artery Smooth Muscle Cells under Oxygen Concentration Gradients and Differences in Their Lung Histology and Expression of Pyruvate Dehydrogenase Kinase 1-Related Factors

Role of Sensory Nerves in Pulmonary Fibrosis

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