N-(2-Aminoethyl) Ethanolamine-Induced Morphological, Biochemical, and Biophysical Alterations in Vascular Matrix Associated With Dissecting Aortic Aneurysm.

Dissecting aortic aneurysm (DAA) is an extended tear in the wall of the aorta along the plane of the vascular media. Our previous studies indicated in a developmental animal model, that DAA was related to pathological alteration in collagen, especially collagen type III. Accordingly, in the present studies, neonatal aortic vascular smooth muscle cells (VSMC) and timed pregnant Sprague-Dawley rat dams were treated with N-(2-aminoethyl) ethanolamine (AEEA), which, as shown previously, causes DAA in offspring. Morphological changes in extracellular matrix (ECM) produced by VSMC in vitro were detailed with scanning electron microscopy (SEM), and biochemical changes in cells and ECM produced by VSMCs were defined by Western blotting. Biophysical changes of the collagen extracted from both the ECM produced by VSMC and extracted from fetal rat aortas were studied with atomic force microscopy (AFM). ECM disruption and irregularities were observed in VSMCs treated with AEEA by SEM. Western blotting showed that collagen type I was much more extractable, accompanied by a decrease of the pellet size after urea buffer extraction in the AEEA-treated VSMC when compared with the control. AFM found that collagen samples extracted from the fetal rat aortas of the AEEA-treated dam, and in the in vitro formed ECM prepared by decellularization, became stiffer, or more brittle, indicating that the 3D organization associated with elasticity was altered by AEEA exposure. Our results show that AEEA causes significant morphological, biochemical, and biomechanical alterations in the ECM. These in vitro and in vivo strategies are advantageous in elucidating the underlying mechanisms of DAA.

Chen Z ，Xu Y ，Bujalowski P ，Oberhauser AF ，Boor PJ ... -  《-》

Dissecting aortic aneurysm induced by N-(2-aminoethyl) ethanolamine in rat: Role of defective collagen during development.

Dissecting aortic aneurysm (DAA) is a tear in the wall of the aorta that causes blood to flow, or "dissect," between the medial layers of the media. Pregnant rats (dams) were treated with the industrial chemical n-(2-aminoethyl) ethanolamine (AEEA) by intraperitoneal injection or gavage. The histology and pathology of aorta in the thorax from newborn pups were examined. Aortas of fetuses of gestational day 20 from dams exposed to AEEA were harvested for immunohistochemical staining and native Western blot to study the changes of collagen type 1 and type 3 in aorta. Dissecting aortic aneurysm of newborn rats was induced by treating with AEEA through intraperitoneal injection or gavage. The incidence of DAA reached 100% in live pups at the high dose by means of gavage of AEEA, but without lethality compared with intraperitoneal injection. A grading system for the dose-response of DAA lesions associated with AEEA by gavage was established. Gestational day 20 fetuses from treated dams showed a decreased content and altered distribution of medial and adventitial collagen type 1 and 3 in aorta by immunohistochemistry; this decrease was confirmed by native Western blot. This in vivo model of spontaneous aortic dissection bears striking similarities histologically to human aortic dissection. As such, the model conceivably could contribute to elucidating the mechanisms of DAA formation and to exploring diagnostic and therapeutic strategies. The pathogenesis of AEEA-induced DAA may be related to defects in the normal developmental progression of collagen types 1 and 3 in the vascular wall.

Xu Y ，Treumann S ，Rossbacher R ，Schneider S ，Boor PJ ... -  《-》

Effects of Extracellular Matrix Softening on Vascular Smooth Muscle Cell Dysfunction.

Shao Y ，Li G ，Huang S ，Li Z ，Qiao B ，Chen D ，Li Y ，Liu H ，Du J ，Li P ... -  《-》

Chemical-induced, nonlethal, developmental model of dissecting aortic aneurysm.

A chemical-induced, nonlethal, dissecting aortic aneurysm (DAA) is described following in utero exposure to semicarbazide, an inhibitor of the vascular enzyme semicarbazide sensitive amine oxidase (SSAO). Sprague-Dawley rat dams were given semicarbazide (0.096-49.000 mg/kg/day) by IP injection on gestation days (GDs) 14-20, a period of rapid aortic development. Newborn rats (day 1) were killed and their thoracic organs were removed en bloc for near-serial cross sections and routine histopathology, Movat stain for elastin, and immunohistochemistry to differentiate cells involved in the evolution of the DAA. In subsequent experiments, pups from treated dams (0.096-6.125 mg/kg/day) were allowed to survive for 7 or 28 days. DAA occurred in nearly 100% of the rats at all doses except the lowest tested (1.530, 0.096 mg/kg/day). Dissections frequently extended to the carotids and, less frequently, to the abdominal aorta. Remodeling of vascular lesions proceeded by organization of collections of blood in vascular media (the "false lumen"), proliferation of vascular smooth muscle cells, fibrosis, and formation of irregular frayed elastic lamellae in healed vascular media. Biochemical quantitation and Western blot analysis of main extracellular matrix proteins on GD 20 showed no overt difference in expression of collagen type I, fibrillin-1, or elastin. This developmental model provides investigators an opportunity to explore the pathologic mechanisms of DAA and to examine the potential long-term effects of vascular remodeling of DAA.

Gong B ，Trent MB ，Srivastava D ，Boor PJ ... -  《birth defects research part a-clinical and molecular teratology》

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections.

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.

Ganizada BH ，Veltrop RJA ，Akbulut AC ，Koenen RR ，Accord R ，Lorusso R ，Maessen JG ，Reesink K ，Bidar E ，Schurgers LJ ... -  《-》