| Autor: |
Jandl K; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Pharmacology and., Marsh LM; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Hoffmann J; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Mutgan AC; Division of Physiology, Otto Loewi Research Center., Baum O; Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Bloch W; German Sports University Cologne, Cologne, Germany; and., Thekkekara-Puthenparampil H; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Kolb D; Gottfried Schatz Research Center., Sinn K; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria., Klepetko W; Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria., Heinemann A; Division of Pharmacology and., Olschewski A; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, and., Olschewski H; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Kwapiszewska G; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Physiology, Otto Loewi Research Center. |
| Abstrakt: |
The extracellular matrix (ECM) increasingly emerges as an active driver in several diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins. In pulmonary arteries, the BM is in close contact and direct proximity to vascular cells, including endothelial cells. So far, the role of the BM has remained underinvestigated in IPAH. Here, we aimed to shed light on the involvement of the BM in IPAH, 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, whereas BM collagens and laminins were more abundantly expressed in IPAH. Type IV collagen and laminin both strengthened endothelial barrier integrity. However, only type IV collagen concentration dependently increased cell adhesion of both donor and IPAH-derived pulmonary arterial endothelial cells (PAECs) and induced nuclear translocation of mechanosensitive transcriptional coactivator of the hippo pathway YAP (Yes-activated protein). On the other hand, laminin caused cytoplasmic retention of YAP in IPAH PAECs. Accordingly, silencing of COL4A5 and LAMC1, respectively, differentially affected tight junction formation and barrier integrity in both donor and IPAH PAECs. Collectively, our results highlight the importance of a well-maintained BM homeostasis. By linking changes in BM structure and composition to altered endothelial cell function, we here suggest an active involvement of the BM in IPAH pathogenesis. |
