Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders

Authors:

Christian Hiepen1, Jerome Jatzlau1 and Petra Knaus1
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Affiliations:

1 Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195 Berlin, Germany.

Keywords: 

BMP, TGFβ, PAH, BMPR2, Integrin, LAP, fibrillin.

Abbreviations:

BMP – Bone Morphogenetic Protein;

BMPR2 – BMP Receptor Type II;

EC – endothelial cell;

ECM – extracellular matrix;

EndMT – endothelial-to-mesenchymal transition;

HHT – hereditary hemorrhagic telangiectasia;

HPAH – hereditary PAH;

iem – internal elastic membrane;

IPAH – idiopathic PAH;

LAP – latency associated peptide;

PAH – Pulmonary Arterial Hypertension.

Corresponding Author(s):

Petra Knaus, Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195 Berlin, Germany; petra.knaus@fu-berlin.de

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Christian Hiepen, Jerome Jatzlau and Petra Knaus (2020). Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders. Cell Stress 4(2): 44-47. doi: 10.15698/cst2020.02.213

© 2020 Hiepen et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

Cardiovascular disorders are still the leading cause for mortality in the western world and challenge economies with steadily increasing healthcare costs. Understanding the precise molecular pathomechanisms behind and identifying players involved in the early onset of cardiovascular diseases remains crucial for the development of new therapeutic strategies. Taking advantage of CRISPR/Cas9 gene editing in human endothelial cells (ECs), we re-investigated the early molecular steps in a genetic vascular disorder termed pulmonary arterial hypertension (PAH) in our recent study (Hiepen C., Jatzlau J. et al.; PLOS Biol, 2019). Here, mutations in the Bone Morphogenetic Protein type II receptor (BMPR2) prime for the hereditary form (HPAH) with downregulated BMPR2 followed by a characteristic change in SMAD signaling, i.e. gain in both SMAD1/5 and SMAD2/3 responses. Remarkably these cells show increased susceptibility to signaling by TGFβ due to remodeling of the extracellular matrix (ECM) and increased biomechanics acting as a secondary stressor for ECs pathobiology. This clearly places BMPR2 not only as a BMP-signaling receptor, but also as a gatekeeper to protect ECs from excess TGFβ signaling.