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.
Keywords: CDH5; VE-cadherin; VEGF-C; VEGFR3; bone marrow; fetal liver; lymphatic; sinusoid.