Endothelial Dysfunction and Mitochondrial Impairement in Hereditary Thoracic Aortic Disease

Objective: Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder and one of the hereditary thoracic aortic diseases (HTAD), caused by pathogenic variants in genes involved in transforming growth factor beta signaling. LDS is associated with aggressive vascular remodeling and a high risk of thoracic aortic aneurysm and dissection. Growing evidence suggests that endothelial dysfunction, including mitochondrial impairment, may contribute to vascular inflammation and weakening of the aortic wall. The aim of this study was to evaluate endothelial dysfunction, microvascular reactivity and mitochondria function patterns in patients with LDS using flow-mediated skin fluorescence (FMSF) as well as to investigate whether SGLT2 inhibitors modulate mitochondrial respiration in primary aortic endothelial cells derived from LDS patients. Design and method: Patients with genetically confirmed LDS carrying pathogenic variants in SMAD3, TGFBR1 and TGFBR2 genes underwent elective cardiac surgery due to advanced aortic dilation. Endothelial function was assessed using FMSF, with emphasis on reactive hyperemia and ischemic response patterns. Endothelial cells were isolated from ascending aorta tissue using magnetic bead-based selection. Mitochondrial respiration and the effects of 24-hour exposure to dapagliflozin or empagliflozin were evaluated using a Seahorse Flex metabolic analyzer. Results: Compared with healthy controls, LDS patients demonstrated impaired endothelial function characterized by decreased reactive hyperemia and an abnormal ischemic response profile, indicating altered microvascular reactivity and potential mitochondrial-related dysfunction. Isolated endothelial cells showed high purity (98-99%) and preserved mitochondrial respiratory stability across passages. In Seahorse assays performed at passage 3, empagliflozin, but not dapagliflozin, improved mitochondrial bioenergetics, increasing basal respiration by approximately 35%. Conclusions: Patients with LDS exhibit clinically detectable endothelial dysfunction by FMSF, including disturbed ischemic response patterns that may reflect impaired mitochondrial-dependent vascular adaptation. Functional studies in patient-derived aortic endothelial cells support the concept that endothelial mitochondrial dysfunction is involved in LDS-associated aortic pathology. Empagliflozin-mediated improvement of mitochondrial respiration highlights endothelial bioenergetics as a potential therapeutic target in HTAD.