Tsukuba, Japan—Due to the sudden rupture of the aortic wall, aortic dissection is a life-threatening condition that requires immediate medical attention, as it can lead to vascular collapse. Individuals with inherited connective tissue disorders, such as Marfan syndrome, are particularly at risk, often developing the condition at a young age. This highlights the urgent need for effective preventive and therapeutic strategies. However, the molecular mechanisms that drive the onset and progression of aortic dissection remain poorly understood.
In a recent study, an international research team led by the University of Tsukuba created a mouse model that spontaneously develops aortic dissection by introducing a missense variant, originally identified in a patient with familial aortic dissection, into the fibrillin-1 (FBN1) gene. This single nucleotide change results in the production of an abnormal fibrillin-1 protein. The mutant mice showed intimal-medial tears in the ascending aorta, with dissection progressing alongside significant infiltration of inflammatory cells. This ultimately led to fatal rupture.
Histological and gene expression analyses revealed that abnormalities in vascular endothelial cells precede the onset of dissection. These endothelial abnormalities facilitated the accumulation and infiltration of monocytes and macrophages into the intima, where the macrophages exhibited both inflammatory and anti-inflammatory phenotypes.
Further investigation indicated that the FBN1 missense variant disrupts the binding of fibrillin-1 to transforming growth factor beta (TGFβ)-binding proteins, leading to reduced TGFβ signaling, a pathway essential for maintaining vascular homeostasis.
These findings suggest that the interaction between vascular endothelial cells and macrophages, along with decreased TGFβ signaling, forms a critical molecular basis for the pathogenesis of aortic dissection. The mouse model developed in this study can serve as a valuable tool for elucidating the molecular mechanisms of aortic dissection and advancing the development of new therapeutic strategies.
