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  BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGFβ responses and altered cell mechanics

Hiepen, C., Jatzlau, J., Hildebrandt, S., Kampfrath, B., Goktas, M., Murgai, A., et al. (2019). BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGFβ responses and altered cell mechanics. PLoS Biology, 17(12): e3000557. doi:10.1371/journal.pbio.3000557.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-7E84-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-7E85-8
Genre: Journal Article

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 Creators:
Hiepen, Christian, Author
Jatzlau, Jerome, Author
Hildebrandt, Susanne, Author
Kampfrath, Branka, Author
Goktas, Melis, Author
Murgai, Arunima1, Author              
Cuellar Camacho, Jose Luis, Author
Haag, Rainer, Author
Ruppert, Clemens, Author
Sengle, Gerhard, Author
Cavalcanti-Adam, Elisabetta Ada, Author
Blank, Kerstin G., Author
Knaus, Petra, Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Abstract: Balanced transforming growth factor-beta (TGFβ)/bone morphogenetic protein (BMP)-signaling is essential for tissue formation and homeostasis. While gain in TGFβ signaling is often found in diseases, the underlying cellular mechanisms remain poorly defined. Here we show that the receptor BMP type 2 (BMPR2) serves as a central gatekeeper of this balance, highlighted by its deregulation in diseases such as pulmonary arterial hypertension (PAH). We show that BMPR2 deficiency in endothelial cells (ECs) does not abolish pan-BMP-SMAD1/5 responses but instead favors the formation of mixed-heteromeric receptor complexes comprising BMPR1/TGFβR1/TGFβR2 that enable enhanced cellular responses toward TGFβ. These include canonical TGFβ-SMAD2/3 and lateral TGFβ-SMAD1/5 signaling as well as formation of mixed SMAD complexes. Moreover, BMPR2-deficient cells express genes indicative of altered biophysical properties, including up-regulation of extracellular matrix (ECM) proteins such as fibrillin-1 (FBN1) and of integrins. As such, we identified accumulation of ectopic FBN1 fibers remodeled with fibronectin (FN) in junctions of BMPR2-deficient ECs. Ectopic FBN1 deposits were also found in proximity to contractile intimal cells in pulmonary artery lesions of BMPR2-deficient heritable PAH (HPAH) patients. In BMPR2-deficient cells, we show that ectopic FBN1 is accompanied by active β1-integrin highly abundant in integrin-linked kinase (ILK) mechano-complexes at cell junctions. Increased integrin-dependent adhesion, spreading, and actomyosin-dependent contractility facilitates the retrieval of active TGFβ from its latent fibrillin-bound depots. We propose that loss of BMPR2 favors endothelial-to-mesenchymal transition (EndMT) allowing cells of myo-fibroblastic character to create a vicious feed-forward process leading to hyperactivated TGFβ signaling. In summary, our findings highlight a crucial role for BMPR2 as a gatekeeper of endothelial homeostasis protecting cells from increased TGFβ responses and integrin-mediated mechano-transduction.

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Language(s): eng - English
 Dates: 2019-11-142019-12-11
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1371/journal.pbio.3000557
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Title: PLoS Biology
  Other : PLoS Biol.
Source Genre: Journal
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Publ. Info: San Francisco, California, US : Public Library of Science
Pages: - Volume / Issue: 17 (12) Sequence Number: e3000557 Start / End Page: - Identifier: ISSN: 1544-9173
CoNE: https://pure.mpg.de/cone/journals/resource/111056649444170