Signal Mechanisms of Vascular Remodeling in the Development of Pulmonary Arterial Hypertension

Li, Mingxing; Jiang, De-qi; Wang, Yan; Chen, Qing-zhuang; Ma, Yue; Yu, Shanshan; Wang, Yong

doi:10.1097/fjc.0000000000000328

Cited by 34 publications

(38 citation statements)

References 95 publications

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“…PDGF is an important growth factor in the development of PAH, stimulating proliferation of PASMCs by activating Stat3 and Akt signal pathways [ 33 , 34 ]. In the present study, inhibition of Shp2 significantly inhibited PDGF-stimulated proliferation and migration of human PASMCs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

Cheng

et al. 2018

BMC Pulm Med

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BackgroundSrc homology 2 containing protein tyrosine phosphatase (PTP) 2 (Shp2) is a typical tyrosine phosphatase interacting with receptor tyrosine kinase to regulate multiple signaling pathways in diverse pathological processes. Here, we will investigate the effect of Shp2 inhibition on pulmonary arterial hypertension (PAH) in a rat model and its potential cellular and molecular mechanisms underlying.MethodsMonocrotaline (MCT)-induced PAH rat model was used in this study. Phps-1, a highly selective inhibitor for Shp2, was administered from 21 days to 35 days after MCT single-injection. Microcatheter method was applied to detected hemodynamic parameters. Histological methods were used to determine PVR changes in PAH rats. Moreover, cultured pulmonary artery smooth muscle cells (PASMCs) treated by platelet-derived growth factor (PDGF) with or without Phps-1 was used to investigate the potential cellular and molecular mechanisms underlying in vitro.ResultsInhibition of Shp2 significantly attenuated MCT-induced increases of mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Shp2 inhibition effectively decreased thickening of pulmonary artery media and cardiomyocyte hypertrophy as well as perivascular and myocardial fibrosis in MCT-treated rats. Moreover, Shp2 inhibition ameliorated muscularization of pulmonary arterioles in MCT-induced PAH rats. Shp2 inhibition significantly reduced platelet-derived growth factor (PDGF)-triggered proliferation and migration of human pulmonary artery smooth muscle cells (PASMCs), which might be attributed to the inactivations of Akt and Stat3 pathways.ConclusionsShp2 contributes to the development of PAH in rats, which might be a potential target for the treatment of PAH.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

Cheng

et al. 2018

BMC Pulm Med

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“…Sustained alveolar hypoxia induces pulmonary vascular remodeling (HPVR) characterized by abnormal thickening of precapillary pulmonary vessel walls and muscularization of small pulmonary arteries [3,4] . Abnormal pulmonary arterial smooth muscle cell (PASMC) proliferation is involved in HPVR due to narrowing of the lumen and an increase in the pulmonary circulatory resistance nally resulting in pulmonary arterial hypertension (PAH) [1,5,6] .…”

Section: Introductionmentioning

confidence: 99%

Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK Signaling Pathways

Tian

Liu

et al. 2020

Preprint

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BACKGROUND: Pulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). Previous studies have found that resistin-like molecule β (RELM-β) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-β has been reported to promote hPASMC proliferation and is involved in pulmonary vascular remodeling in patients with PAH. However, the expression pattern, effects, and mechanisms of action of RELM-β in HPH remain unclear.METHODS: We assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-β in a rat HPH model and in hPASMCs.RESULTS: Overexpression of RELM-β caused hemodynamic changes in a rat model of HPH similar to those induced by chronic hypoxia, including increased mean right ventricular systolic pressure (mRVSP), right ventricular hypertrophy index (RVHI) and thickening of small pulmonary arterioles. Knockdown of RELM-β partially blocked the increases in mRVSP, RVHI, and vascular remodeling induced by hypoxia. The phosphorylation levels of the PI3K, Akt, mTOR, PKC, and MAPK proteins were significantly up- or downregulated by RELM-β gene overexpression or silencing, respectively. Recombinant RELM-β protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-β on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor.CONCLUSIONS: Our findings suggest that RELM-β acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-β are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

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“…It is widely known that pulmonary arterial smooth muscle cell(PASMC) proliferation is involved in hypoxia-induced vascular remodeling. PASMC proliferation narrows the lumen and increases resistance in the pulmonary vascular, finally resulting in pulmonary arterial hypertension(PAH) [1,5,6] .…”

Section: Introductionmentioning

confidence: 99%

Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via Ca2+ dependent PI3K/Akt/mTOR and PKC/MAPKs Signaling Pathway

Tian

Liu

Yin

et al. 2020

Preprint

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BACKGROUND: Pulmonary arterial smooth muscle cells(PASMCs) proliferation plays a crucial role in Hypoxia-induced pulmonary hypertension(HPH). Previous studies have found that Resistin-like molecule β(RELM-β) up-regulated de novo in response to hypoxia in cultured primary human PASMCs(HASMCs). RELM-β has been proved to promote PASMCs proliferation and involved in pulmonary vascular remodeling of patients with PAH. However, the expression pattern, the effects, and the mechanisms of RELM-β in HPH keep unknown. METHODS: We assessed the expression pattern, mitogenetic effect, and underlying mechanism of RELM-β in the rat HPH model and HASMCs. RESULTS: Overexpression of RELM-β alone caused the hemodynamic change in the rat model of HPH, similar to that caused by chronic hypoxia, with increased mean pulmonary arterial pressure(mPAP), right ventricle hypertrophy(RVSP), and thickening of small pulmonary arterioles. Knocking down of RELM-β partially blocked the increased mPAP, RVSP, and vascular remodeling induced by hypoxia. Phosphorylated PI3K/Akt/mTOR and PKC/MAPKs proteins were significantly up- or down-regulated by RELM-β gene overexpression or silencing. Recombinant RELM-β protein increase primary cultured human PASMCs intracellular Ca 2+ concentration and promote HASMCs proliferation. The mitogenic effect of RELM-β on HASMCs and phosphorylated PI3K/Akt/mTOR and PKC/MAPKs was suppressed by Ca 2+ inhibitor. CONCLUSIONS: Our findings suggested that RELM-β acts as a cytokine-like growth factor in the development of HPH and that this process is likely mediated by the Ca 2+ dependent PI3K/Akt/mTOR and PKC/MAPKs pathway. Keywords : hypoxic pulmonary arterial hypertension; resistin-like molecule β; Ca 2+ ; pulmonary vascular remodeling; signaling pathway

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Signal Mechanisms of Vascular Remodeling in the Development of Pulmonary Arterial Hypertension

Cited by 34 publications

References 95 publications

Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK Signaling Pathways

Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via Ca2+ dependent PI3K/Akt/mTOR and PKC/MAPKs Signaling Pathway

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