Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1-Endoglin-Smad1/5/9 signalling

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation Pub Date : 2024-04-09 DOI:10.1111/eci.14212

Chunyong Yang, Mei Sun, Yihui Yang, Yan Han, Xiulin Wu, Xianfeng Wu, Huilin Cao, Lin Chen, Yuhao Lei, Xiaoyan Hu, Yang Chen, Ziyang Zeng, Junhong Li, Xin Shu, Zhiyong Yang, Kaizhi Lu, Yujie Li, Xiaobo Wang, Bin Yi

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Abstract

Background

Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS.

Methods

We profiled the circulating BMP9 levels in common bile duct ligation-induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells.

Results

Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor-like kinase1 (ALK1)-Endoglin-Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1-Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro-angiogenic monocytes in the microvasculature in HPS rats.

Conclusions

This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1-Endoglin-Smad1/5/9 pathway. In addition, BMP9-regulated pathways are also involved in accumulation of pro-angiogenic monocytes in the pulmonary microvasculature in HPS rats.

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循环 BMP9 升高会通过 ALK1-Endoglin-Smad1/5/9 信号加重肝肺综合征大鼠的肺血管生成

背景骨形态发生蛋白 9（BMP9）是一种肝脏因子，在肝脏疾病的进展中起着关键作用。此外，越来越多的研究表明，BMP9 与肝肺综合征（HPS）有关，但其在 HPS 中的作用尚不清楚。在此，我们评估了 CBDL 对 BMP9 表达的影响，并研究了 BMP9 信号在 HPS 中的潜在机制。方法我们分析了胆总管结扎诱导的 HPS 大鼠模型中的循环 BMP9 水平，然后研究了 HPS 大鼠血清对大鼠模型肺血管内皮功能障碍的影响和机制，以及对主要培养的大鼠肺微血管内皮细胞的影响和机制。此外，HPS 大鼠血清中升高的 BMP9 不仅是通过激活素受体样激酶 1（ALK1）-Endoglin-Smad1/5/9 途径促进内皮细胞增殖和管道形成的关键，而且对单核细胞的聚集也很重要。使用 ALK1-Fc 或沉默 ALK1 表达以抑制 BMP9 信号通路，可有效消除这些影响。与这些观察结果一致的是，循环 BMP9 的增加与 HPS 大鼠肺血管密度的增加和微血管中促血管生成单核细胞的聚集有关。此外，BMP9调节的途径还参与了HPS大鼠肺微血管中促血管生成单核细胞的聚集。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Clinical Investigation 医学-医学：内科

CiteScore

9.50

自引率

3.60%

发文量

192

审稿时长

1 months

期刊介绍： EJCI considers any original contribution from the most sophisticated basic molecular sciences to applied clinical and translational research and evidence-based medicine across a broad range of subspecialties. The EJCI publishes reports of high-quality research that pertain to the genetic, molecular, cellular, or physiological basis of human biology and disease, as well as research that addresses prevalence, diagnosis, course, treatment, and prevention of disease. We are primarily interested in studies directly pertinent to humans, but submission of robust in vitro and animal work is also encouraged. Interdisciplinary work and research using innovative methods and combinations of laboratory, clinical, and epidemiological methodologies and techniques is of great interest to the journal. Several categories of manuscripts (for detailed description see below) are considered: editorials, original articles (also including randomized clinical trials, systematic reviews and meta-analyses), reviews (narrative reviews), opinion articles (including debates, perspectives and commentaries); and letters to the Editor.