Modulating effective lymphatic drainage in aortic adventitia has anti-atherosclerotic effects: a new mechanism of FOXC2 to improve lymphatic endothelial cells inflammatory damage

Abstract Atherosclerosis is a chronic multifactorial cardiovascular disease. The disruption of lymphatic drainage function, which is induced by inflammatory damage to lymphatic endothelial cells (LECs), plays an essential role in atherosclerosis. However, the detailed regulatory mechanisms remain largely unknown. Since FOXC2 has become a major regulator of lymphatic vessel development and maturation, we explored the possibility that FOXC2 contributes to lymphatic drainage and atherosclerosis. Herein, we identified FOXC2 mitigates atherosclerosis by restoring efficiently lymphatic drainage via regulating LECs inflammatory responses. Atherosclerosis leds to aortic lymphatic drainage dysfunction, and an down-regulation of FOXC2 expression in the aorta, especially in aortic adventitia, and an inhibition of the biological activity of FOXC2. FOXC2 overexpression improved the aortic lymphatic drainage function which led to reducing the accumulation of inflammatory factors in aortic adventitia, lymph nodes and lymphatic fluid. However, disruption of lymph flow by left carotid artery ligation abrogated the beneficial effects by FOXC2 overexpression on atherosclerosis. Western blot and co-immunoprecipitation experiment revealed that TRAF2 as a key downstream target in TNF-α-induced LECs inflammatory damage. FOXC2 overexpression down-regulated TRAF2, inhibited interaction of TNF-α with TRAF2, reduced the inflammatory damage to LECs, and restored LECs functions, which promoted the function of lymphatic drainage. FOXC2 knockout aggravated TNF-α-induced LECs inflammatory damage, TRAF2 up-regulation, and increased TNF-α interaction with TRAF2. Collectively, we have demonstrated that FOXC2 serves a central role in the atherogenesis induced by lymphatic drainage dysfunction.