Lymphangiogenesis in Abdominal Aortic Aneurysm regulates the balance between resident and circulating eosinophils via a 15-lipoxygenase-dependent mechanism

Abstract

The abdominal aortic aneurysm (AAA) is a chronic degeneration of the aortic wall involving an inflammatory response, aberrant remodeling of the extracellular matrix, and the development of microvessels. Among these, lymphatic capillaries develop in the adventitia. However, the role of lymphangiogenesis in AAA remains unclear. Here, we confirmed the development of lymphatic vessels in both human and mouse AAA. This was associated with a decrease in specialized pro-resolving mediators (SPM) generated by 15-Lipoxygenase (15LO), an enzyme that controls resolution of inflammation in lymphatic diseases. Lymphatic selective depletion of 15LO (Prox1cre; Alox15fl/fl mice) increased both systemic and resident eosinophil (EOS) accumulation in lesions, but had no effect on other immune cell populations. Mechanistically, in vitro depletion of 15LO in lymphatic endothelial cells (LEC) significantly decreased EOS adhesion. In contrast, 15LO LEC depletion improved transendothelial migration. In vivo, the rescue of 15LO using lentivector transduction modified the balance between resident and systemic EOS in favor of the resident ones and reduced the AAA lesion. Altogether, we show that lymphatic vessels play a protective role in AAA by regulating the trafficking of EOS into the aorta wall.