Sung Derek C, Chen Mei, Dominguez Martin H, Mahadevan Aparna, Chen Xiaowen, Yang Jisheng, Gao Siqi, Ren Aileen A, Tang Alan T, Mericko Patricia, Patton Raiyah, Lee Michelle, Jannaway Melanie, Nottebaum Astrid, Vestweber Dietmar, Scallan Joshua P, Kahn Mark L
Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
University Laboratory Animal Resources, University of Pennsylvania, Philadelphia, Pennsylvania.
Nat Cardiovasc Res. 2022 Nov;1(11):1006-1021. doi: 10.1038/s44161-022-00147-0. Epub 2022 Nov 11.
Sinusoids are specialized, low pressure blood vessels in the liver, bone marrow, and spleen required for definitive hematopoiesis. Unlike other blood endothelial cells (ECs), sinusoidal ECs express high levels of VEGFR3. VEGFR3 and its ligand VEGF-C are known to support lymphatic growth, but their function in sinusoidal vessels is unknown. In this study, we define a reciprocal VEGF-C/VEGFR3-CDH5 (VE-cadherin) signaling axis that controls growth of both sinusoidal and lymphatic vessels. Loss of VEGF-C or VEGFR3 resulted in cutaneous edema, reduced fetal liver size, and bloodless bone marrow due to impaired lymphatic and sinusoidal vessel growth. Mice with membrane-retained VE-cadherin conferred identical lymphatic and sinusoidal defects, suggesting that VE-cadherin opposes VEGF-C/VEGFR3 signaling. In developing mice, loss of VE-cadherin rescued defects in sinusoidal and lymphatic growth caused by loss of VEGFR3 but not loss of VEGF-C, findings explained by potentiated VEGF-C/VEGFR2 signaling in VEGFR3-deficient lymphatic ECs. Mechanistically, VEGF-C/VEGFR3 signaling induces VE-cadherin endocytosis and loss of function via SRC-mediated phosphorylation, while VE-cadherin prevents VEGFR3 endocytosis required for optimal receptor signaling. These findings establish an essential role for VEGF-C/VEGFR3 signaling during sinusoidal vascular growth, identify VE-cadherin as a powerful negative regulator of VEGF-C signaling that acts through both VEGFR3 and VEGFR2 receptors, and suggest that negative regulation of VE-cadherin is required for effective VEGF-C/VEGFR3 signaling during growth of sinusoidal and lymphatic vessels. Manipulation of this reciprocal negative regulatory mechanism, e.g. by reducing VE-cadherin function, may be used to stimulate therapeutic sinusoidal or lymphatic vessel growth.
肝血窦是肝脏、骨髓和脾脏中特化的低压血管，是确定的造血过程所必需的。与其他血管内皮细胞（EC）不同，肝血窦内皮细胞高水平表达血管内皮生长因子受体3（VEGFR3）。已知VEGFR3及其配体血管内皮生长因子C（VEGF-C）可支持淋巴管生长，但其在肝血窦血管中的功能尚不清楚。在本研究中，我们定义了一个相互作用的VEGF-C/VEGFR3-钙黏蛋白5（VE-钙黏蛋白）信号轴，该信号轴控制肝血窦和淋巴管的生长。VEGF-C或VEGFR3缺失导致皮肤水肿、胎儿肝脏大小减小以及骨髓无血，这是由于淋巴管和肝血窦血管生长受损所致。具有膜保留型VE-钙黏蛋白的小鼠表现出相同的淋巴管和肝血窦缺陷，这表明VE-钙黏蛋白与VEGF-C/VEGFR3信号传导相反。在发育中的小鼠中，VE-钙黏蛋白缺失挽救了由VEGFR3缺失而非VEGF-C缺失引起的肝血窦和淋巴管生长缺陷，这一发现可通过VEGFR3缺陷的淋巴管内皮细胞中VEGF-C/VEGFR2信号增强来解释。从机制上讲，VEGF-C/VEGFR3信号传导通过SRC介导的磷酸化诱导VE-钙黏蛋白内吞和功能丧失，而VE-钙黏蛋白可防止最佳受体信号传导所需的VEGFR3内吞。这些发现确立了VEGF-C/VEGFR3信号传导在肝血窦血管生长过程中的重要作用，确定VE-钙黏蛋白是通过VEGFR3和VEGFR2受体发挥作用的VEGF-C信号的强大负调节因子，并表明在肝血窦和淋巴管生长过程中，有效的VEGF-C/VEGFR3信号传导需要对VE-钙黏蛋白进行负调节作用。操纵这种相互的负调节机制，例如通过降低VE-钙黏蛋白功能，可用于刺激治疗性肝血窦或淋巴管生长。
