Divergent and Compensatory Effects of BMP2 and BMP4 on the VSMC Phenotype and BMP4's Role in Thoracic Aortic Aneurysm Development.
Daniel KlessingerArgen MamazhakypovSophie GlaeserRamona EmigRémi PeyronnetLena MeierKora ProelssKatia MarenneChristian SmolkaSebastian GrundmannFranziska PankratzPhilipp R EsserMartin MoserQian ZhouJennifer Susanne EsserPublished in: Cells (2024)
Vascular smooth muscle cells (VSMCs) play a key role in aortic aneurysm formation. Bone morphogenetic proteins (BMPs) have been implicated as important regulators of VSMC phenotype, and dysregulation of the BMP pathway has been shown to be associated with vascular diseases. The aim of this study was to investigate for the first time the effects of BMP-4 on the VSMC phenotype and to understand its role in the development of thoracic aortic aneurysms (TAAs). Using the angiotensin II (AngII) osmotic pump model in mice, aortas from mice with VSMC-specific BMP-4 deficiency showed changes similar to AngII-infused aortas, characterised by a loss of contractile markers, increased fibrosis, and activation of matrix metalloproteinase 9. When BMP-4 deficiency was combined with AngII infusion, there was a significantly higher rate of apoptosis and aortic dilatation. In vitro, VSMCs with mRNA silencing of BMP-4 displayed a dedifferentiated phenotype with activated canonical BMP signalling. In contrast, BMP-2-deficient VSMCs exhibited the opposite phenotype. The compensatory regulation between BMP-2 and BMP-4, with BMP-4 promoting the contractile phenotype, appeared to be independent of the canonical signalling pathway. Taken together, these results demonstrate the impact of VSMC-specific BMP-4 deficiency on TAA development.
Keyphrases
- mesenchymal stem cells
- bone regeneration
- vascular smooth muscle cells
- angiotensin ii
- magnetic resonance imaging
- heart failure
- skeletal muscle
- spinal cord
- magnetic resonance
- cell proliferation
- low dose
- oxidative stress
- cell death
- left ventricular
- aortic valve
- spinal cord injury
- computed tomography
- pulmonary hypertension
- smoking cessation
- binding protein
- aortic dissection
- bone loss