The lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage 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 proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions.

中文翻译：

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AIBP-CAV1-VEGFR3轴决定了淋巴细胞的命运并控制淋巴管生成

淋巴管对于维持组织液的动态平衡至关重要。因此，淋巴功能障碍导致淋巴水肿。在发展中，淋巴管生成通常需要来自静脉EC的淋巴管内皮细胞（LEC）谱系规范，以及随后的LEC增殖和迁移，所有这些都受VEGFC / VEGFR3信号传导的调节。胆固醇对于正常的细胞功能和器官发育至关重要，但胆固醇代谢控制淋巴管生成的分子机制尚不清楚。我们表明，分泌的蛋白，ApoA1结合蛋白（AIBP），通过加速胆固醇外流决定了淋巴管的形成。斑马鱼中人类旁系同源物Aibp2的缺失会损害LEC祖细胞的规格并阻碍淋巴管生成。机械上，我们发现小窝蛋白1（CAV-1）抑制LEC中的VEGFR3活化，并且AIBP调节的胆固醇外流破坏脂质筏/小窝并降低CAV-1的生物利用度，从而取消了CAV-1对VEGFR3信号的抑制，从而增强了VEGFR3。激活并增加淋巴管生成。用ApoA1过表达增强胆固醇外流或使用阿托伐他汀抑制胆固醇生物合成可恢复Aibp2突变斑马鱼的正常淋巴管生成。Cav-1的丢失增加了斑马鱼的LEC祖细胞规格，并挽救了Aibp2缺陷动物的淋巴管生成。重组AIBP补充剂在小鼠胚胎干细胞（mESC）中赋予LEC分化模型深刻的LEC命运承诺。此外，AIBP-CAV-1-VEGFR3信号轴的增强可促进VEGFC参与的成年小鼠淋巴管生成。与这些数据一致，AIBP表达在人淋巴水肿皮肤的表皮中减少。这些研究表明，AIBP介导的胆固醇外流是淋巴管生成的关键因素。我们的研究将为淋巴功能障碍的治疗提供一条新的治疗途径。