Abstract 13674: AIBP-Mediated Cholesterol Efflux Controls Lymphangiogenesis

Background: Lymphangiogenesis give rise to lymphatic vessels that are essential for maintenance of tissue fluid homeostasis. Lymphatic vessel formation requires lymphatic endothelial cell (LEC) specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for cell functions and organ development yet the molecular mechanism by which it controls lymphangiogenesis is unknown. Hypothesis: In this study, we hypothesize the role of apoA-I binding protein (AIBP)-regulated cholesterol metabolism in lymphangiogenesis. Aim: We aim to dissect the role of AIBP mediated cholesterol efflux on caveolin-1 (CAV-1) disruption and its effect on VEGFC/VEGFR3 signaling and lymphangiogenesis. Methods: We utilized the mouse embryonic stem cell differentiation model to assess the role of AIBP-CAV-1-VEGFR3 axis in LEC fate determination. We used AIBP and CAV-1 knockout (KO) to assess the role of this signaling circuit in developmental lymphangiogenesis using zebrafish and in adult lymphangiogenesis using the mouse corneal lymphangiogenesis model. We used CAV-1 KO neonatal mice to study tail lymphangiogenesis. Results: We found that AIBP dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the zebrafish paralog of human AIBP, impairs lymphangiogenesis. Recombinant AIBP protein induces mouse embryonic stem cell differentiation to LECs. Mechanistically, CAV-1 suppresses VEGFR3 activation, but cholesterol efflux by AIBP disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation in human LECs. Loss of CAV-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. CAV-1 KO neonatal mice significantly augmented tail lymphangiogenesis. Further, AIBP expression is reduced in the epidermis of human lymphedema. Conclusion: Our study elucidates a novel role of AIBP-mediated cholesterol efflux in lymphatic vessel formation and provides new therapeutic targets for the treatment of lymphatic dysfunctions.