Sex-related differences in wall remodeling and intraluminal thrombus resolution in a rat saccular aneurysm model
Authors: Graziano Pelli
Henning Richter
Philippe Bijlenga
Vincent Braunersreuther
Sandrine Morel
Juhana Frösen
Katja M Nuss
Esther Sutter
Brenda R Kwak
Vanessa Graf
Agnieszka Karol
Journal: Journal of neurosurgery (2019)
Discipline: CLINICAL MEDICINE
Keywords: endothelium; human; intracranial aneurysm; rat; sex differences
Affiliations: 1Department of Pathology and Immunology and, 3Musculoskeletal Research Unit and, 4Diagnostic Imaging Research Unit, Vetsuisse Faculty, University of Zürich, Switzerland; and, 5Division of Clinical Pathology, Diagnostic Department, Geneva University Hospitals, Geneva;, 6Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland, 2Division of Neurosurgery, Department of Clinical Neurosciences, Faculty of Medicine, and

Abstract:  Objective: Intracranial aneurysms (IAs) are more often diagnosed in women. Hormones and vessel geometry, which influences wall shear stress, may affect pathophysiological processes of the arterial wall. Here, the authors investigated sex-related differences in the remodeling of the aneurysm wall and in intraluminal thrombus resolution. Methods: A well-characterized surgical side-wall aneurysm model was used in female, male, and ovariectomized rats. Decellularized grafts were used to model highly degenerated and decellularized IA walls and native grafts to model healthy IA walls. Aneurysm growth and thrombus composition were analyzed at 1, 7, 14, and 28 days. Sex-related differences in vessel wall remodeling were compared with human IA dome samples of men and pre- and postmenopausal women. Results: At 28 days, more aneurysm growth was observed in ovariectomized rats than in males or non-ovariectomized female rats. The parent artery size was larger in male rats than in female or ovariectomized rats, as expected. Wall inflammation increased over time in all groups and was most severe in the decellularized female and ovariectomized groups at 28 days compared with the male group. Likewise, in these groups the most elastin fragmentation was seen at 28 days. In female rats, on days 1, 7, and 14, the intraluminal thrombus was mainly composed of red blood cells and fibrin. On days 14 and 28, macrophage and smooth muscle cell invasion inside the thrombus was shown, leading to the removal of red blood cells and deposition of collagen and elastin. On days 14 and 28, similar profiles of thrombus reorganization were observed in male and ovariectomized female rats. However, collagen content in thrombi and vessel wall macrophage content were higher in aneurysms of male rats at 28 days than in those of female rats. On day 28, thrombus coverage by endothelial cells was lower in ovariectomized than in female or male rats. Finally, analysis of human IA domes showed that endothelial cell coverage was lower in men and postmenopausal women than in younger women. Conclusions: Aneurysm growth and intraluminal thrombus resolution show sex-dependent differences. While certain processes (endothelial cell coverage and collagen deposition) point to a strong hormonal dependence, others (wall inflammation and aneurysm growth) seem to be influenced by both hormones and parent artery size. 

Retracted: No

PubPeer comments:
 FIg 2A and Fig 2B display aortic diameter measured using two different methods (MRI ex vivo histology). Yet the values displayed for male rats (columns M) are surprisingly similar (identical?). Likely a copy past error but it would be good if the authors could comment. Imgur: https: imgur.com a raQm4ds , 
 The values in the  M columns of Fig2A and 2B seem surprisingly similar despite the use of different methods. Perhaps the authors could comment? Fig 2A: ![file] Fig 2B: ![file] ,