肺动脉(PAs)细胞外基质的变化是肺动脉高压(PH)血管重塑的关键方面。然而,我们对影响蛋白聚糖(PG)家族的改变的理解仍然有限。我们试图调查来自健康个体和各种PH组的PA中主要血管PGs的表达和空间分布(慢性阻塞性肺疾病:PH-COPD,肺纤维化:PH-PF,特发性:IPAH)。PG调节,沉积,IPAH的合成显著提高,其次是PH-PF,PH-COPD有轻微改变。单细胞分析揭示了细胞类型和疾病特异性PG调节。Agrin表达,基底膜PG,在IPAH中增加了,PA内皮细胞(PAECs)被确定为主要来源。PA平滑肌细胞(PASMCs)主要产生大PG,aggrecan和versican,和小亮氨酸样蛋白聚糖(SLRP)双糖,而外膜成纤维细胞产生的主要PG是SLRP核心蛋白聚糖和lumican。在IPAH和PF-PH中,新内膜形成PASMC群体增加了所有研究的大PGs和SLRP的表达,除了成纤维细胞占优势的DCN。lumican的表达,versican,IPAH和PH-PF患者PASMC中胶原蛋白1α1/1α2的表达也呈正相关。我们证明TGF-β调节versican和biglycan的表达,表明它们对IPAH和PF-PH中血管纤维化的贡献。我们还表明,某些循环PG水平显示出疾病依赖性模式,随着所有患者群体中decorin和lumican的增加,而versican在PH-COPD和IPAH中升高,而biglycan在IPAH中降低。这些发现表明,在不同形式的PH中,独特的区室特异性PG调节,表明不同的病理过程。
Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and
versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican,
versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-β) regulates
versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while
versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes.NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and
versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation.