An Myh11 single lysine deletion causes aortic dissection by reducing aortic structural integrity and contractility

Area of Science:

• Cardiovascular Biology
• Genetics and Genomics
• Translational Medicine

Background:

• Familial thoracic aortic aneurysms and dissections (FTAAD) are linked to pathogenic variants in myosin heavy chain (Myh11).
• The precise pathological mechanisms driving FTAAD remain incompletely understood due to a lack of suitable animal models.

Purpose of the Study:

• To establish and characterize a novel mouse model mimicking human FTAAD caused by a specific Myh11 pathogenic variant (K1256del).
• To elucidate the cellular and molecular mechanisms underlying aortic pathology in this model.

Main Methods:

• Generation of a mouse model harboring the Myh11 K1256del variant (Myh11^∆K/∆K).
• Histological and ultrastructural analysis of aortic tissues.
• Pharmacological stimulation with angiotensin II to induce aortic events.
• Assessment of cell adhesion molecule expression (Itga2) and smooth muscle cell differentiation from induced pluripotent stem cells.
• Measurement of aortic contractility.

Main Results:

• Myh11^∆K/∆K aortas exhibited increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion.
• Myh11^∆K/+ mice developed aortic dissections and intramural hematomas upon angiotensin II stimulation.
• Downregulation of integrin subunit alpha2 (Itga2) was observed in Myh11^∆K/∆K aortas.
• Reduced aortic contractility was noted in Myh11^∆K/∆K aortas, linked to impaired cell adhesion.

Conclusions:

• The Myh11 K1256del variant leads to aortic pathology through mechanisms involving weakened cell adhesion and defective aorta contraction.
• This mouse model provides critical insights into FTAAD pathogenesis, highlighting the role of Myh11 in maintaining aortic integrity and function.