Pulmonary arterial hypertension (PAH) is a vascular disease that is characterized by elevated pulmonary arterial pressure (PAP) due to progressive vascular remodeling. Extracellular matrix (ECM) deposition in pulmonary arteries (PA) is one of the key features of vascular remodeling. Emerging evidence indicates that the basement membrane (BM), a specialized cluster of ECM proteins underlying the endothelium, may be actively involved in the progression of vascular remodeling. The BM and its steady turnover are pivotal for maintaining appropriate vascular functions. However, the pathologically elevated turnover of BM components leads to an increased release of biologically active short fragments, which are called matrikines. Both BM components and their matrikines can interfere with pivotal biological processes, such as survival, proliferation, adhesion, and migration and thus may actively contribute to endothelial dysfunction. Therefore, in this review, we summarize the emerging role of the BM and its matrikines on the vascular endothelium and further discuss its implications on lung vascular remodeling in pulmonary hypertension.

Acute respiratory inflammation, most commonly resulting from bacterial or viral infection, is one of the leading causes of death and disability worldwide. The inflammatory lipid mediator prostaglandin D₂ (PGD₂) and its rate-limiting enzyme, hematopoietic PGD synthase (hPGDS), are well-known drivers of allergic pulmonary inflammation. Here, we sought to investigate the source and role of hPGDS-derived PGD₂ in acute pulmonary inflammation. Murine bronchoalveolar monocytes/macrophages from LPS- but not OVA-induced lung inflammation released significant amounts of PGD₂. Accordingly, human monocyte-derived macrophages expressed high basal levels of hPGDS and released significant levels of PGD₂ after LPS/IFN-γ, but not IL-4 stimulation. Human peripheral blood monocytes secreted significantly more PGD₂ than monocyte-derived macrophages. Using human precision-cut lung slices (PCLS), we observed that LPS/IFN-γ but not IL-4/IL-13 drive PGD₂ production in the lung. HPGDS inhibition prevented LPS-induced PGD₂ release by human monocyte-derived macrophages and PCLS. As a result of hPGDS inhibition, less TNF-α, IL-6 and IL-10 could be determined in PCLS-conditioned medium. Collectively, this dataset reflects the time-dependent release of PGD₂ by human phagocytes, highlights the importance of monocytes and macrophages as PGD₂ sources and suggests that hPGDS inhibition might be a potential therapeutic option for acute, non-allergic lung inflammation.

The extracellular matrix (ECM) increasingly emerges as an active driver in several pulmonary diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins, which underlies all endothelial cells. Despite this close contact, the role of the BM in IPAH, and its impact on endothelial function, has remained under-investigated. In this study, we aimed to shed light on the involvement of the BM in PAH, by addressing its structure, composition and function. On an ultrastructural level, we observed a marked increase in BM thickness in IPAH pulmonary vessels. BM composition was distinct in small and large vessels and altered in IPAH: Proteoglycans were mostly responsible for distinction between smaller and larger vessels, while BM collagens and laminins were more abundantly expressed in IPAH. Seeding donor or IPAH derived pulmonary arterial endothelial cells (PAEC) on collagen IV- or laminin coated surfaces strengthened endothelial barrier integrity as quantified by electrical impedance measurement, however only type IV collagen increased cell adhesion and induced nuclear translocation of mechanosensitive transcriptional co-activator of the hippo pathway Yes-activated protein (YAP). Opposingly, laminin induced cytoplasmic retention of YAP in IPAH PAEC, which, inherently, presented with increased YAP activation levels. Here we show that changes in BM structure and composition have a profound bearing on endothelial cell function, and suggest that changes of the BM may play a role in the pathogenesis of IPAH.