Protective role of Pannexin1 in lymphatic endothelial cells in the progression of atherosclerosis in female mice
Extracted from Fig 4A. Females have larger atherosclerotic plaques in aortic roots after 6 weeks of HCD. Sudan-IV staining of female control Panx1fl/flApoe-/- mice, female Panx1LECdelApoe-/-, male control Panx1fl/flApoe-/- mice and male Panx1LECdelApoe-/- mice after 6 weeks of HCD. Scale bar represents 200 μm. ©2024 Avigail EHRLICH et al/UNIGE
SUMMARY
Atherosclerosis is a progressive arterial disease arising from imbalanced lipid metabolism and a maladaptive immune response. The lymphatic system ensures tissue fluid homeostasis, absorption of dietary fats and trafficking of immune cells to draining lymph nodes, thereby potentially affecting atherogenesis. Endothelial cell-specific deletion of Pannexin1 (Panx1) in apolipoprotein E-deficient (Apoe-/-) mice increased atherosclerosis, suggesting a protective role for Panx1 channels in arterial endothelial function. Here, the authors investigated the role of Panx1 in lymphatic endothelial cells (LECs) in the initiation and the progression of atherosclerosis. Male or female Prox1-CreERT2+Panx1fl/flApoe-/- and Panx1fl/flApoe-/- mice were fed a high cholesterol diet (HCD) for 6 or 10 weeks. Tamoxifen-induced deletion of Panx1 was performed before or after 4 weeks of HCD. Body weight and serum lipid profiles were determined. The atherosclerotic plaque burden was assessed by Sudan-IV staining on thoracic-abdominal aortas and in aortic roots. Plaque composition was determined by immunohistochemistry. No differences in serum cholesterol, LDL and HDL were observed between genotypes and between sexes after HCD. Bodyweight, serum triglycerides and free fatty acid levels were higher before and after 6 weeks of HCD in male Prox1-CreERT2+Panx1fl/flApoe-/- and control Panx1fl/flApoe-/- mice compared to females of the same genotypes, which was associated with more lipids and inflammatory cells in their atherosclerotic plaques. In contrast, the atherosclerotic plaque burden was higher in female mice. The progression of atherosclerosis in male mice was not different between genotypes. However, female Prox1-CreERT2+Panx1fl/flApoe-/- mice showed enhanced progression of atherosclerosis compared to Panx1fl/flApoe-/- controls of the same sex. In addition, atherosclerotic lesions in female, but not in male, Prox1-CreERT2+Panx1fl/flApoe-/- mice showed T cell enrichment. Altogether, these results reveal differential sex-dependent effects of Panx1 in lymphatic endothelium on the progression of atherosclerosis.
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Why is it important?
Atherosclerosis is a chronic arterial disease characterised by lipid deposition and inflammation, leading to plaque formation. The lymphatic system, critical for fluid homeostasis, fat transport, and immune cell trafficking, may influence atherogenesis. This study investigated the role of Pannexin1 (Panx1), a membrane channel-forming protein, in lymphatic endothelial cells (LECs). Female mice lacking Panx1 in LECs exhibited increased atherosclerotic plaque burden and immune cell infiltration, suggesting Panx1 exerts a protective effect in females. Male mice did not show this response. These findings highlight sex-specific mechanisms in cardiovascular disease progression and identify Panx1 as a potential therapeutic target.
14 Jan 2025