The Kong Wei/Cong Xin research group and collaborators developed a new MRI early warning probe for thoracic aortic aneurysm/dissection based on tight endothelial connection

Thoracic aortic aneurysm/dissection is a highly lethal form of cardiovascular disease
.
The early onset is insidious and the patient has no obvious symptoms, and once the tumor/dissection ruptures, the mortality rate is as high as 80%, ranking first
among cardiovascular critical diseases.
At present, the understanding of the pathogenesis of thoracic aortic aneurysm/dissection mainly focuses on stromal remodeling, smooth muscle cell contraction and mechanical conduction abnormalities, while the role of endothelium, as the first line of defense of blood vessels, has been rarely reported
。 Given that the barrier formed by tight junctions between adjacent endothelial cells plays an important role in determining vascular homeostasis, can altered endothelial barrier function lead to thoracic aortic aneurysm/dissection? In this study, single-cell sequencing was performed using samples from patients with thoracic aortic aneurysm/dissection, and it was found that the junction score in endothelial cells showed a downward trend compared with the control group, and the expression of a variety of tight junction molecules was reduced, suggesting that abnormal endothelial tight junction may be involved in the occurrence
of thoracic aortic aneurysm/dissection 。 Then, β-aminopropionitrile (BAPN) was used to induce a mouse thoracic aortic aneurysm/dissection model, and it was found that the expression of tight junction molecules in the thoracic aorta was reduced in the early stage.
Through the tracer molecular permeability experiments of Evans blue and dextran two paracellular pathways, it was found that the endothelial cell permeability of the ascending aorta and descending aorta was significantly increased.
Transmission electron microscopy showed that the tight connection distance of the ascending aorta was significantly increased compared with that of the control group.
En face staining showed reduced membrane localization of the tight junction molecules ZO-1 and claudin-5 in the ascending and descending aorta, suggesting impaired
endothelial barrier function in the early stage of thoracic aortic aneurysm/dissection.

The existing early prediction methods for thoracic aortic aneurysm/dissection are mainly monitored by imaging of the aortic diameter of patients, but only 8% of patients with aortic dissection will have dilated blood vessels before aortic tear, so there is still a lack of early and effective warning indicators
.
Based on the above findings, we linked two barrier functional indicators of different molecular weights (dexturoside (4 and 70 kDa) with the NMR contrast metal element Gd to synthesize novel endothelial barrier functional NMR detection probes, named FDD-Gd and RDD-Gd
。 Through the MRI detection of BAPN-induced mice at different times, it was found that the contrast intensity of the vascular wall of the two probes was significantly higher than that of the control group when the diameter of the thoracic aorta had not changed in the early stage, and the mice with continuous increase in contrast enhancement developed thoracic aortic aneurysm/dissection at the end of the experiment, while the mice with no continuous increase in contrast intensity did not develop the disease
.
This suggests that the probe provides an early prediction
of thoracic aortic aneurysm/dissection.

In order to clarify the mechanism of action between changes in endothelial tight junction function and thoracic aortic aneurysm/dissection, we used the drug prazolepeptide acetate (also known as AT-1001, which has entered the US FDA Phase III clinical trial for the treatment of celiac disease), which has been shown to enhance the function of the tight junction in vivo and in vitro experiments, and found that AT-1001 can significantly reduce the incidence of thoracic aortic aneurysm/dissection and improve the survival rate
of mice 。 The flow cytometry results showed that BAPN induced a significant increase in the number of CD45+ leukocytes, CD11b+ Ly6G+ neutrophils and CD11b+ Ly6C+ Ly6G- neutrophils in early vascular tissues of mice, while AT-1001 treatment reversed this phenomenon
.
In addition, vascular weighing and glycosaminoglycan staining found that BAPN induced an increase in early thoracic aortic edema in mice, while AT-1001 treatment reduced the degree of
angioedema.
The above suggests that disruption of the endothelial tight junction barrier can lead to the development
of thoracic aortic aneurysm/dissection by increasing inflammatory cell infiltration and angioedema.

In this study, single-cell sequencing, vascular permeability evaluation and magnetic resonance imaging were used to clarify that vascular endothelial tight junction expression and dysfunction are early events in the development of thoracic aortic aneurysm/dissection, and the new probe synthesized based on the detection of endothelial barrier function can be used as an early warning indicator of thoracic aortic aneurysm/dissection, and the use of tight junction sealant can significantly reduce the incidence of
disease.
This discovery provides new ideas and targets for the early diagnosis and treatment of thoracic aortic aneurysm/dissection
, a dangerous cardiovascular disease.

Dr.
Xueyuan Yang and Dr.
Chen Xu of Beijing University of Chemical Technology are co-first authors of the paper, Professor Wei Kong and Associate Professor Xin of the Department of Physiology and Pathophysiology of Peking University School of Basic Medical Sciences, and Professor Fujian Xu of Beijing University of Chemical Technology are co-corresponding authors
.
The work was also supported and helped
by Professor Wang Li of Fuwai Hospital of Chinese Academy of Medical Sciences, Professor Ma Qingchuan of Peking University Third Hospital and Professor Zhu Junming of Beijing Anzhen Hospital.
The research was supported by the National Natural Science Foundation of China
, the Innovation Group and the National Key R&D Program.

Original link: https://doi.
org/10.
1093/eurheartj/ehac823
.