在肺动脉高血压中通过血管内皮生长因子受体3调节内皮骨形态蛋白受体2型活性
Cheol Hwangbo1, Heon-Woo Lee1, Hyeseon Kang1
1From Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (C.H., H.-W.L., H.K., H.J., I.P., J.H., J.-D.K., W.P.D., X.H., S.L., O.E.-H., A.S., H.J.C., S.-W.J.); Department of Biology, University of North Carolina, Chapel Hill (D.S.W., V.L.B.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (B.P., S.-W.J.); Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, OH (L.P., S.C., S.C.E.); Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul (E.M.H., J.-Y.P.); School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul (J.-Y.P.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); and Université Pierre and Marie Curie-Paris 6, CRICM, Groupe Hospitalier Pitié-Salpètrière, France; INSERM, UMRS 975, Groupe Hospitalier Pitié-Salpètrière, Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, Paris, France (J.-L.T.).
血管内皮生长因子受体3 (VEGFR3) 调节骨形态蛋白受体2型 (BMPR2) 信号,影响肺动脉高血压 (PAH) 的发展. 在PAH细胞中恢复VEGFR3改善了BMP信号,确定VEGFR3是PAH的关键因素.
科学领域:
- 心血管生物学
- 分子医学
- 内皮细胞生物学
背景情况:
- 骨形态蛋白 (BMP) 信号传递对血管发育和功能至关重要.
- 在家族性肺动脉高血压 (PAH) 中,BMP受体2型 (BMPR2) 突变很常见,但并非所有携带者都会患上这种疾病.
- 这表明其他因素会改变BMPR2的功能,并影响PAH的发病和进展.
研究的目的:
- 研究血管内皮生长因子受体3 (VEGFR3) 和BMPR2之间的相互作用.
- 确定VEGFR3在BMP信号传递中的作用及其对肺高血压的影响.
主要方法:
- 对斑马鱼胚胎和小鼠进行内皮特异性Vegfr3缺失的研究.
- 使用人体内皮细胞 (包括PAH患者的初级肺内皮细胞) 的体外研究.
- 评估了VEGFR3和BMPR2之间的物理关联,以及下游信号事件.
主要成果:
- 斑马鱼中的Vegfr3衰减导致BMP诱导的血管生成受损.
- 缺乏VEGFR3的内皮细胞对BMP刺激的反应受损.
- VEGFR3与BMPR2进行物理相互作用,促进其内细胞和随后的SMAD酸化.
- 在小鼠中,Vegfr3的内皮缺失加剧了低氧引起的肺高血压.
- 在人类肺动脉内皮细胞中观察到VEGFR3表达的减少.
- 在PAH细胞中恢复VEGFR3,使BMP信号正常化.
结论:
- VEGFR3是内皮BMPR2信号的关键调节者.
- 在具有BMPR2突变的个体中,VEGFR3表达水平可能是PAH透性的决定因素.
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