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

Ming-Yuan Liu; Meili Wang; Junjun Liu; An-Qiang Sun; Chang-Shun He; Xin Cong; Wei Kong; Wei Li

doi:10.1016/j.jpha.2024.101120

Volume 15 Issue 2

Feb. 2025

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Ming-Yuan Liu, Meili Wang, Junjun Liu, An-Qiang Sun, Chang-Shun He, Xin Cong, Wei Kong, Wei Li. Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome[J]. Journal of Pharmaceutical Analysis, 2025, 15(2): 101120. doi: 10.1016/j.jpha.2024.101120

Citation:

Ming-Yuan Liu, Meili Wang, Junjun Liu, An-Qiang Sun, Chang-Shun He, Xin Cong, Wei Kong, Wei Li. Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome[J]. Journal of Pharmaceutical Analysis, 2025, 15(2): 101120. doi: 10.1016/j.jpha.2024.101120

Citation:

Ming-Yuan Liu, Meili Wang, Junjun Liu, An-Qiang Sun, Chang-Shun He, Xin Cong, Wei Kong, Wei Li. Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome[J]. Journal of Pharmaceutical Analysis, 2025, 15(2): 101120. doi: 10.1016/j.jpha.2024.101120

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

doi: 10.1016/j.jpha.2024.101120

a. Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Center of Vascular Surgery, Beijing, 100050, China;
b. Department of Vascular Surgery, Peking University People's Hospital, Beijing, 100044, China;
c. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China;
d. Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China;
e. School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China;
f. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China;
g. The Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant Nos.: 82000429 and 81470574), Young Elite Scientists Sponsorship Program by CAST, China (Program No.: YESS20230395/2023QNRC001), Beijing Nova Program, China (Program No.: 20230484308), Youth Elite Program of Beijing Friendship Hospital, China (Program No.: YYQCJH2022-9), Young Elite Scientists Sponsorship Program by BAST, China (Program No.: BYESS2024045), Capital's Funds for Health Improvement and Research, China (Grant No.: CFH2022-4-20217), and Chinese Institutes for Medical Research, Beijing (CIMR) Organized Research Project, China (Project No.: CX23YQ07).

Received Date: Mar. 27, 2024
Accepted Date: Oct. 10, 2024
Rev Recd Date: Sep. 19, 2024
Publish Date: Oct. 28, 2024

Abstract

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.
- Thoracic aortic aneurysm (TAA),
- mTORC1,
- Marfan syndrome,
- Biomechanicalpathogenesis,
- Wall shear stress (WSS)

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References(45)

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