Universität zu Köln

Hiepen, Christian ORCID: 0000-0001-7345-6496, Jatzlau, Jerome ORCID: 0000-0002-1757-0267, Hildebrandt, Susanne, Kampfrath, Branka, Goktas, Melis, Murgai, Arunima ORCID: 0000-0001-9767-7402, Camacho, Jose Luis Cuellar, Haag, Rainer, Ruppert, Clemens, Sengle, Gerhard, Cavalcanti-Adam, Elisabetta Ada, Blank, Kerstin G. and Knaus, Petra (2019). BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGF beta responses and altered cell mechanics. PLoS. Biol., 17 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1545-7885

Full text not available from this repository.

Abstract

Balanced transforming growth factor-beta (TGF beta)/bone morphogenetic protein (BMP)-signaling is essential for tissue formation and homeostasis. While gain in TGF beta 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/TGF beta R1/TGF beta R2 that enable enhanced cellular responses toward TGF beta. These include canonical TGF beta-SMAD2/3 and lateral TGF beta-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 beta 1-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 TGF beta 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 TGF beta signaling. In summary, our findings highlight a crucial role for BMPR2 as a gatekeeper of endothelial homeostasis protecting cells from increased TGF beta responses and integrin-mediated mechano-transduction.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hiepen, Christian UNSPECIFIED orcid.org/0000-0001-7345-6496 UNSPECIFIED Jatzlau, Jerome UNSPECIFIED orcid.org/0000-0002-1757-0267 UNSPECIFIED Hildebrandt, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Kampfrath, Branka UNSPECIFIED UNSPECIFIED UNSPECIFIED Goktas, Melis UNSPECIFIED UNSPECIFIED UNSPECIFIED Murgai, Arunima UNSPECIFIED orcid.org/0000-0001-9767-7402 UNSPECIFIED Camacho, Jose Luis Cuellar UNSPECIFIED UNSPECIFIED UNSPECIFIED Haag, Rainer UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruppert, Clemens UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Cavalcanti-Adam, Elisabetta Ada UNSPECIFIED UNSPECIFIED UNSPECIFIED Blank, Kerstin G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knaus, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-125538
DOI:	10.1371/journal.pbio.3000557
Journal or Publication Title:	PLoS. Biol.
Volume:	17
Number:	12
Date:	2019
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1545-7885
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR-BETA; PULMONARY-ARTERY SMOOTH; TO-MESENCHYMAL TRANSITION; KINASE 1 ALK1; ACTIVIN RECEPTOR; MUSCLE-CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; MYOFIBROBLAST DIFFERENTIATION; EXTRACELLULAR-MATRIX; MEDIATED REGULATION Multiple languages Biochemistry & Molecular Biology; Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12553