Endothelial Basement Membrane Components and Their Products, Matrikines: Active Drivers of Pulmonary Hypertension?

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  Figure 1. Possible mode of action of matrikines on pulmonary arterial endothelial cells. Type IV collagen matrikines alter cell survival in endothelial cells. Arresten and canstatin activate Fas-L-mediated apoptosis (caspase 8 activation) via an unknown mechanism [154,155]. Upon integrin binding, arresten, canstatin, and tumstatin induce caspase-9 dependent mitochondrial apoptosis via inhibiting FAK phosphorylation [114,153,154,166]. Canstatin and tumstatin attenuate proliferation by inhibiting the FAK/PI3K/AKT/mTOR signaling pathway [114,153]. BM HSPGs influence cell survival and cell motility. Endostatin and endorepellin activate autophagy in a Beclin1-dependent manner [158,159]. In addition, endostatin and endorepellin trigger the disassembly of actin stress fibers by inhibiting caveolin-associated Src-mediated RhoA kinase [164] and by activating the FAK/p38/HSP27 signaling pathway [165], respectively. Hence, matrikines can interfere with crucial EC functions involved in PH pathophysiology. Receptors and signaling proteins involved in the depicted pathways, but not directly investigated in the indicated studies, are represented in gray. Fas-L, Fas ligand; FAK, focal adhesion kinase;…

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  Figure 2. Current knowledge on the role of basement membrane components in pulmonary endothelial cell function in IPAH. In IPAH, the structure and composition of the BM is altered [4]. In PAs, COL4A5, COL14A1, COL18A1, perlecan, agrin, and versican levels are increased [5,174,175]. In the circulation, increased levels of endostatin, matrikine of type XVIII collagen α1, are found, which correlates with disease severity and survival [5,41]. In ECs of PAH patients, COL4A1 and COL4A2 are reduced [173]. COL4A1 and COL4A2 are downstream targets of BMPR2, as reduced levels of BMPR2 and β-catenin lead to decreased COL4A1 and COL4A2 expression, resulting in impaired migration and adhesion [173,176]. The culture of PAEC on type IV collagen and laminin strengthen barrier and integrity. While adhesion to type IV collagen triggers nuclear translocation of YAP/TAZ, adhesion to laminin α5β2γ1 retains YAP/TAZ in the cytoplasm [4]. Endostatin blocks ID-1 gene expression and decreases THBS1-transcription and production [177]. In return, TSP-1 inhibits pulmonary EC proliferation and migration via CD36/CD47, suggesting an endostatin–ID1–TSP1 axis [177]. IPAH; idiopathic pulmonary arterial hypertension; BM,…