Mechanotransduction in Marfan Syndrome and Related Aortic Disorders: Insights from Transcriptomic Analyses

Area of Science:

• Cardiovascular Biology
• Genetics
• Biotechnology

Background:

• Heritable thoracic aortic diseases (HTADs) are genetically diverse disorders leading to aortic aneurysm and dissection.
• Current therapies only slow disease progression, not prevent aortic wall failure.
• Genetic defects disrupt the aorta's mechanobiological systems, affecting cellular communication and integrity.

Purpose of the Study:

• To review the current understanding of HTAD pathogenesis, focusing on mechanobiological disruptions.
• To synthesize insights from genetic variants, cellular responses, and signaling pathways.
• To explore therapeutic opportunities based on systems-level approaches.

Main Methods:

• Review of existing literature on HTADs, Marfan syndrome as a model.
• Analysis of single-cell transcriptomics to understand cell-type-specific changes.
• Integration of data on biomechanics, signaling pathways, and immune responses.

Main Results:

• Genetic defects converge to disrupt aortic wall mechanobiological homeostasis.
• Altered biomechanics, signaling (e.g., TGF-β, nitric oxide), and immune responses drive aneurysm formation.
• Single-cell analyses reveal cell-specific changes in ECM degradation, iron metabolism, and stress responses.

Conclusions:

• HTAD progression involves a multicellular failure of mechanobiological homeostasis.
• Cell-type-specific pathogenic programs and metabolic changes are implicated.
• Developing precise, mechanism-based therapies requires considering disease stage, cellular context, and intervention timing.