Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling caused by plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. Objective: We sought to test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. Methods: We used digital spatial transcriptomics to profile the genomewide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n = 11) and compared these data with the intima+media hypertrophy and adventitia of control pulmonary artery (n = 5). Measurements and Main Results: We detected 8,273 transcripts in the IPAH lesions and control lung pulmonary arteries. Plexiform lesions and IPAH adventitia exhibited the greatest number of differentially expressed genes when compared with intima+media hypertrophy and obliterative lesions. Plexiform lesions in IPAH showed enrichment for 1) genes associated with transforming growth factor β signaling and 2) mutated genes affecting the extracellular matrix and endothelial-mesenchymal transformation. Plexiform lesions and IPAH adventitia showed upregulation of genes involved in immune and IFN signaling, coagulation, and complement pathways. Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. Conclusions: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.

中文翻译：

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数字空间分析可识别肺动脉高压血管病变的独特分子特征。


理由：特发性肺动脉高压（IPAH）的特点是丛状和闭塞性病变、中膜肥厚、炎性细胞浸润和外膜改变引起的广泛肺血管重塑。目的：我们试图检验这样的假设：显微 IPAH 血管病变表达独特的分子特征，这些特征总体上与对照肺动脉不同。方法：我们使用数字空间转录组学来分析 IPAH 肺部 (n = 11) 关键病理病变（丛状病变、闭塞性病变、内膜+中膜肥厚和外膜）的全基因组差异转录组特征，并将这些数据与内膜+中膜肥厚和外膜病变进行比较。对照肺动脉外膜 (n = 5)。测量和主要结果：我们在 IPAH 病变和对照肺肺动脉中检测到 8,273 个转录本。与内膜+中膜肥厚和闭塞性病变相比，丛状病变和 IPAH 外膜表现出最多数量的差异表达基因。 IPAH 中的丛状病变显示出 1) 与转化生长因子 β 信号传导相关的基因和 2) 影响细胞外基质和内皮间质转化的突变基因的富集。丛状病变和 IPAH 外膜显示参与免疫和 IFN 信号、凝血和补体途径的基因上调。细胞解卷积表明 IPAH 病变之间血管和炎症细胞数量的差异，这是差异转录谱分析的基础。 结论：IPAH 病变表达独特的分子转录谱，丰富了涉及致病途径的途径，包括遗传性疾病驱动因素、先天性和获得性免疫、缺氧感知和血管生成信号传导。这些数据提供了 IPAH 血管病变丰富的分子结构框架，为这种高度发病性疾病的新生物标志物和治疗靶点提供了信息。