Thakur Abhijeet, Clair Geremy, Zhang Liang, Soni Sourabh, Mariani Thomas J, Çataltepe Sule
Brigham and Women's Hospital, Department of Pediatric Newborn Medicine, Boston, Massachusetts, United States.
Harvard Medical School, Boston, Massachusetts, United States.
Am J Respir Cell Mol Biol. 2025 Aug 22. doi: 10.1165/rcmb.2025-0009OC.
Bronchopulmonary dysplasia is a chronic lung disease that affects preterm infants. Disrupted microvascular growth is a well-recognized pathologic feature of BPD, which plays a critical role in arrested alveologenesis. Recent studies have identified two subpopulations of pulmonary microvascular endothelial cells (ECs): general capillary (gCap) and aerocyte (aCap). In this study, we validated proposed markers for gCap (GPIHBP1, PLVAP, CD93) and aCap (CA4, HPGD) at the protein level and investigated their abundance during late-stage lung development in murine and non-human primate (NHP) lungs. We also examined alterations in the abundance and proliferation of gCap and aCap in NHP and murine models of BPD. Our studies confirmed CA4 and HPGD as specific markers for aCap, while all three putative gCap markers were also detected in non-microvascular endothelial cells. All markers, except for HPGD, showed a gradual increase in abundance during the saccular and alveolar stages of development in NHP lungs. In the NHP model of BPD, the abundance of both aCap markers and GPIHBP1 were decreased, while that of PLVAP and CD93 were increased. Additionally, there was an emergence of CA4HPGD-aCap in BPD lungs. In late-stage control lungs, aCap proliferation was more robust than gCap proliferation, while no significant differences were observed between aCap and gCap proliferation rates in NHP BPD. Notably, in BPD lungs, gCap proliferation was more robust compared to control lungs. This study provides new insights into the distinct regulation patterns of microvascular ECs during lung development and neonatal lung injury in a translationally relevant NHP model.
支气管肺发育不良是一种影响早产儿的慢性肺部疾病。微血管生长紊乱是支气管肺发育不良公认的病理特征，在肺泡生成停滞中起关键作用。最近的研究确定了肺微血管内皮细胞（ECs）的两个亚群：普通毛细血管（gCap）和气囊细胞（aCap）。在本研究中，我们在蛋白质水平验证了gCap（GPIHBP1、PLVAP、CD93）和aCap（CA4、HPGD）的拟用标志物，并研究了它们在小鼠和非人类灵长类动物（NHP）肺晚期发育过程中的丰度。我们还检查了NHP和支气管肺发育不良小鼠模型中gCap和aCap的丰度及增殖变化。我们的研究证实CA4和HPGD是aCap的特异性标志物，而所有三种假定的gCap标志物在非微血管内皮细胞中也有检测到。除HPGD外，所有标志物在NHP肺发育的囊状和肺泡阶段丰度逐渐增加。在支气管肺发育不良的NHP模型中，aCap标志物和GPIHBP1的丰度降低，而PLVAP和CD93的丰度增加。此外，支气管肺发育不良的肺中出现了CA4HPGD-aCap。在晚期对照肺中，aCap增殖比gCap增殖更强，而在NHP支气管肺发育不良中，aCap和gCap增殖率之间未观察到显著差异。值得注意的是，在支气管肺发育不良的肺中，gCap增殖比对照肺更强。这项研究为在与转化相关的NHP模型中肺发育和新生儿肺损伤期间微血管内皮细胞的不同调控模式提供了新见解。
