一般毛细血管内皮细胞通过HIF-2α/Notch4通路在肺高血压中被重新编程成动脉内皮细胞
Bin Liu1,2,3, Dan Yi1,2,3, Xiaomei Xia1,2
1Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, Arizona, USA.
bioRxiv : the preprint server for biology
|March 11, 2024
概括
在肺动脉高血压 (PAH) 中,肺毛细血管细胞通过HIF-2a-Notch4通路转化为动脉细胞. 针对这种转变为PAH患者提供了潜在的新疗法.
科学领域:
- 心血管生物学 心血管生物学
- 肺部医学 肺部医学
- 细胞生物学 细胞生物学
背景情况:
- 肺动脉高血压 (PAH) 涉及肺血管抵抗和重塑的增加,导致右心力衰竭.
- 在PAH中远端毛细血管内皮细胞 (EC) 损失和血管损伤形成背后的机制尚未完全理解.
研究的目的:
- 研究PAH中推动肺血管重塑的细胞机制.
- 在PAH的背景下确定动脉ECs的细胞起源.
- 基于EC行为来探索PAH的潜在治疗点.
主要方法:
- 在人类PAH患者和动物模型上单细胞RNA测序和空间转录组学.
- RNASCOPE和用于EC表征的免疫染色.
- 在记者小鼠中的毛细血管EC特异性血统追踪.
- 对HIF-2a的遗传删除和对Notch4.4的药理抑制.
主要成果:
- 在人类PAH和动物模型中,有动脉EC积累和毛细血管EC损失的证据.
- 伪药分析表明,在肺高血压 (PH) 发育过程中,毛细血管EC转变为动脉EC.
- 鉴定出CXCL12是PH中动脉EC标志物.
- 血统追踪证实了毛细血管EC在PH中产生动脉EC.
- 在PH中,HIF-2a删除或Notch4抑制逆转了动脉编程.
结论:
- 在PAH发育过程中,毛细血管内皮通过HIF-2a-Notch4通路过渡到动脉内皮.
- 针对这种动脉EC过渡,为PAH提供了一个新的治疗策略.
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