Dysregulation of BMP9/BMPR2/SMAD signalling pathway contributes to pulmonary fibrosis and pulmonary hypertension induced by bleomycin in rats

Qian, Jiang; Liu, Chunli; Liu, Shiyun; Lu, Wenju; Li, Yi; Luo, Xiaoning; Ma, Ran; Zhang, Chenting; Chen, Hạixia; Chen, Yuqin; Zhang, Zizhou; Hong, Cheng; Guo, Wenliang; Wang, Tao; Yang, Kai; Jian, Wang

doi:10.1111/bph.15285

Cited by 34 publications

(25 citation statements)

References 47 publications

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Section: Discussionmentioning

confidence: 99%

“…Loss of function SMAD9 mutations have been reported as an infrequent cause of PAH and restoration of SMAD9 functioning could decrease proliferation of PAH smooth muscle cells. [20][21][22] Sanada et al 23 recently examined TGF and SMAD levels in human PAH as well as animal models of PAH. By immunofluorescent staining, TGFRb1 was not different in the SU5416H model vs. controls, but TGFRb2 was increased in pulmonary vessels.…”

Section: Discussionmentioning

confidence: 99%

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SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

2021

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Introduction: SU5416 plus chronic hypoxia causes pulmonary arterial hypertension (PAH) in rats and is assumed to occur through VEGFR2 inhibition. Cabozantinib is a far more potent VEGFR2 inhibitor than SU5416. Therefore, we hypothesized that cabozantinib plus hypoxia would induce severe PAH in rats. Methods: Cell proliferation and pharmacokinetic studies were performed. Rats were given SU5416 or cabozantinib SC or via osmotic pump and kept hypoxic for 3 weeks. Right ventricular systolic pressure (RVSP) and hypertrophy (RVH) were evaluated at day 14 and 28 following removal from hypoxia. RV fibrosis was evaluated with Picro-Sirius Red staining. Kinome inhibition profiles of SU5416 and cabozantinib were performed. Inhibitor binding constants of SU5416 and cabozantinib for BMPR2 were determined and Nanostring analyses of lung mRNA were performed. Results: Cabozantinib was a more potent VEGFR inhibitor than SU5416 and had a longer half-life in rats. Cabozantinib SC plus hypoxia did not induce severe PAH. RVSP at 14 and 28d post-hypoxia was 36.8 Â± 2.3 mmHg and 36.2 Â± 3.4 mmHg, respectively, versus 27.5 Â± 1.5 mmHg in normal controls. For cabozantinib given by osmotic pump during hypoxia, RVSP was 40.0 Â± 3.1 mmHg at 14d and 27.9 Â± 1.9 mmHg at 28d post-hypoxia. SU5416 plus hypoxia induced severe PAH (RVSP 61.9 Â± 6.1 mmHg and 64.9 Â± 8.4 mmHg at 14d and 28d post-hypoxia, respectively). Cabozantinib induced less RVH (RV/(LV+IVS) at 14d post-hypoxia compared to SU5416. RV fibrosis was more extensive in the SU5416 groups compared to the Cabozantinib groups. SU5416 (but not cabozantinib) inhibited BMPR2. Nanostring analyses showed effects on pulmonary gene expression of BMP10 and VEGFR1 in the SU5416 28 day post hypoxia group. Conclusion: Selective VEGFR2 inhibition using cabozantinib plus hypoxia did not induce severe PAH. Severe PAH due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

2021

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“…Therapeutic strategies targeting the pulmonary endothelial BMP9/BMPR2/SMAD signaling pathway can be an option for treatment for this subtype of PH in the future. 27 …”

Section: Animal Studies On Pulmonary Hypertensionmentioning

confidence: 99%

Recent Advances and Future Prospects of Treatment of Pulmonary Hypertension

Hajra¹,

Safiriyu²,

Balasubramanian³

et al. 2023

Current Problems in Cardiology

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“…68,69 Bleomycin-induced downregulation of BMP9/BMPR2/Smad signaling in the PA endothelium may act as a trigger to induce PH, suggesting novel therapeutic strategies for the treatment of this subtype of PH. 63…”

Section: Bleomycinmentioning

confidence: 99%

Experimental animal models of pulmonary hypertension: Development and challenges

Ding

et al. 2022

Anim Models and Exp Med

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Pulmonary hypertension (PH) is a severe, progressive vascular disorder characterized by elevation in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), finally leading to right heart failure and death. During the rise in PAP and PVR, vascular remodeling is accompanied by accumulation of pulmonary artery smooth muscle cells (PASMCs), endothelial cells (ECs), fibroblasts, myofibroblasts and pericytes in pulmonary arterial wall, which leads to thickening of the inner and outer linings of blood vessels, loss and obstructive remodeling of the pulmonary vascular bed and perivascular inflammation. 1-3 Associated with multiple primary causes, PH encompasses a group of clinical entities. According to the latest classification proposed by the Sixth World Symposium on PH, the disease can develop due to pulmonary arterial disorder, left heart disease, lung disease or hypoxia, chronic thromboembolic disease and other unclear or multifactorial mechanisms. 4 Though current treatments can improve clinical symptoms and hemodynamic abnormality to some extent, it is difficult to target pulmonary vascular remodeling and

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Dysregulation of BMP9/BMPR2/SMAD signalling pathway contributes to pulmonary fibrosis and pulmonary hypertension induced by bleomycin in rats

Cited by 34 publications

References 47 publications

SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

Recent Advances and Future Prospects of Treatment of Pulmonary Hypertension

Experimental animal models of pulmonary hypertension: Development and challenges

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