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Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay
Published on: September 14, 2021
Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders
Christian Hiepen1, Jerome Jatzlau1, Petra Knaus1
1Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195 Berlin, Germany.
Insights
Mutations in Bone Morphogenetic Protein type II receptor (BMPR2) cause pulmonary arterial hypertension (PAH). BMPR2 downregulation increases TGFβ signaling, impacting endothelial cell pathobiology and cardiovascular disease progression.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Biology
Background:
- Cardiovascular disorders are a leading cause of mortality and rising healthcare costs.
- Understanding molecular mechanisms in early cardiovascular disease onset is vital for new therapies.
- Pulmonary arterial hypertension (PAH) is a severe genetic vascular disorder.
Purpose of the Study:
- To investigate the early molecular steps in hereditary PAH (HPAH) using CRISPR/Cas9 gene editing.
- To elucidate the role of Bone Morphogenetic Protein type II receptor (BMPR2) in PAH.
- To understand how BMPR2 mutations affect endothelial cell (EC) signaling and pathobiology.
Main Methods:
- CRISPR/Cas9 gene editing in human endothelial cells (ECs).
- Analysis of SMAD signaling pathways (SMAD1/5 and SMAD2/3).
- Investigation of extracellular matrix (ECM) remodeling and biomechanics.
Main Results:
- Mutations in BMPR2 lead to its downregulation, priming for HPAH.
- Downregulated BMPR2 alters SMAD signaling, with increased SMAD1/5 and SMAD2/3 responses.
- ECs with BMPR2 mutations exhibit increased susceptibility to TGFβ signaling due to ECM remodeling and biomechanics.
Conclusions:
- BMPR2 functions not only as a BMP receptor but also as a crucial gatekeeper against excessive TGFβ signaling in ECs.
- BMPR2 dysfunction is a key factor in the pathobiology of PAH.
- These findings offer insights into therapeutic strategies for cardiovascular diseases, particularly PAH.
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.
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