Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Jandl, K; Marsh, LM; Hoffmann, J; Mutgan, AC; Baum, O; Bloch, W; Thekkekara-Puthenparampil, H; Kolb, D; Sinn, K; Klepetko, W; Heinemann, A; Olschewski, A; Olschewski, H; Kwapiszewska, G.
Basement Membrane Remodeling Controls Endothelial Function in Idiopathic Pulmonary Arterial Hypertension.
Am J Respir Cell Mol Biol. 2020; 63(1):104-117
Doi: 10.1165/rcmb.2019-0303OC
Web of Science
PubMed
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- Leading authors Med Uni Graz
- Jandl Katharina
- Kwapiszewska-Marsh Grazyna
- Co-authors Med Uni Graz
- Heinemann Akos
- Hoffmann Julia
- Kolb Dagmar
- Marsh Leigh
- Mutgan Redolfi Ayse Ceren
- Olschewski Andrea
- Olschewski Horst
- Thekkekara Puthenparampil Helene
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Basement Membrane - metabolism
- Basement Membrane - physiopathology
- Collagen Type IV - metabolism
- Endothelial Cells - metabolism
- Endothelial Cells - physiology
- Extracellular Matrix - metabolism
- Extracellular Matrix - physiology
- Extracellular Matrix Proteins - metabolism
- Familial Primary Pulmonary Hypertension - metabolism
- Familial Primary Pulmonary Hypertension - physiopathology
- Female -
- Humans -
- Laminin - metabolism
- Male -
- Proteoglycans - metabolism
- Pulmonary Artery - metabolism
- Pulmonary Artery - physiopathology
- Find related publications in this database (Keywords)
- extracellular matrix
- vascular remodeling
- type IV collagen
- laminin
- barrier function