Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome

TL;DR

This study reveals how disturbed blood flow and mTORC1 activation contribute to aortic aneurysms in Marfan syndrome, offering new treatment strategies.

Contribution

The study identifies mTORC1 activation by oscillatory wall shear stress as a novel biomechanical driver of thoracic aortic aneurysms in Marfan syndrome.

Findings

Disturbed flow-induced OSS activates mTORC1 in smooth muscle cells, promoting TAA progression.

Rapamycin treatment reduces mTORC1 activity, attenuating TAA in an MFS mouse model.

mTORC1 activation is directly linked to the intensity of OSS in TAA development.

Abstract

Thoracic aortic aneurysm (TAA) significantly endangers the lives of individuals with Marfan syndrome (MFS), yet the intricacies of their biomechanical origins remain elusive. Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA, with a particular emphasis on the mechanistic contributions of the mammalian target of rapamycin (mTOR) signaling cascade. We uncovered that activation of the mTOR complex 1 (mTORC1) within smooth muscle cells, instigated by the oscillatory wall shear stress (OSS) that stems from disturbed flow (DF), is a catalyst for TAA progression. This revelation was corroborated through both an MFS mouse model (Fbn1+/C1039G) and clinical MFS specimens. Crucially, our research demonstrates a direct linkage between the activation of the mTORC1 pathway and the intensity in OSS. Therapeutic administration of rapamycin suppresses mTORC1 activity, leading to the attenuation of aberrant SMC behavior, reduced inflammatory infiltration, and restoration of extracellular matrix integrity—collectively decelerating TAA advancement in our mouse model. These insights posit the mTORC1 axis as a strategic target for intervention, offering a novel approach to manage TAAs in MFS and potentially pave insights for current treatment paradigms.

Biomechanical Approach of Thoracic Aortic Aneurysm ExpansionImage 1

Biomechanical Approach of Thoracic Aortic Aneurysm Expansion

•The biomechanical mechanism of TAA remains unclear compared to physiological factors.•Disturbed flow induced OSS activates mTORC1 pathway, leading to phenotype switch in aortic smooth muscle cells.•This work offers biomechanical-based therapeutic insights for TAA treatment.

The biomechanical mechanism of TAA remains unclear compared to physiological factors.

Disturbed flow induced OSS activates mTORC1 pathway, leading to phenotype switch in aortic smooth muscle cells.

This work offers biomechanical-based therapeutic insights for TAA treatment.

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