Expression of the lymphangiogenic reelin is associated with sex-dependent calcific aortic stenosis in men

Abstract

Background and aims: Aortic stenosis is a major form of adult valvulopathy with strong sex-related phenotypes. Circulating reelin, a large extracellular glycoprotein, regulates lymphangiogenesis and inflammation and promotes atherosclerosis, a risk factor in aortic stenosis. We sought to investigate the sex-dependent expression of reelin in stenotic aortic valves to comprehend its role in aortic stenosis progression.

Methods: Reelin was studied in aortic valves and serum samples from severe aortic stenosis and aortic regurgitation patients. In vitro calcification modelling of human valve interstitial cells (VICs) (n = 18 donors, 50 % men) was conducted for 2, 4 and 8 days.

Results: Reelin (RELN) expression was enhanced within the fibrocalcific areas of stenotic aortic valves, especially in men. Expression of RELN was associated with angiogenic and lymphangiogenic, inflammation and osteogenic markers only in aortic stenosis but not in aortic regurgitation. The VIC, along with inflammatory cells and valve endothelial cells, expressed reelin. In vitro, we confirmed the VIC to display sex-dependent responses as those reported within the valve. Male VICs expressed higher RELN than women's, and that was significantly associated with enhanced Dab2/Akt/NFkB signaling as well as with lymphangiogenesis, inflammation, and osteogenesis markers.

Conclusions: This study suggests a sex-dependent expression of reelin in stenotic aortic valves. This observation is partly due to different responses in VIC between men and women. In men, reelin was associated with inflammation, angiogenesis, lymphangiogenesis, and osteogenesis, which contributes to more calcific phenotypes, clinically relevant in male patients. However, further mechanistic studies are necessary to fully understand these processes. It's important to note that these findings were not reflected in circulating levels of reelin.

Keywords: Angiogenesis; Aortic valve stenosis; Calcification; Inflammation; Reelin; Sex differences; Valve interstitial cell.