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Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):603-15. doi: 10.1161/ATVBAHA.113.303053. Epub 2014 Jan 9.

AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses.

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From the Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (H.J.Z., X.C., Q.H., H.Z., Y.W., Y.J., W.M.); State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China (H.J.Z., X.C., X.L., L.L.); Diseases of the Aorta Lab, Center for the Endothelium, Vascular Biology Program, Centenary Institute and University of Sydney, Sydney, Australia (R.L.); Department of Ophthalmology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China (Z.X.).



To investigate the novel function of ASK1-interacting protein-1 (AIP1) in vascular endothelial cell growth factor receptor (VEGFR)-3 signaling, and VEGFR-3-dependent angiogenesis and lymphangiogenesis.


AIP1, a signaling scaffold protein, is highly expressed in the vascular endothelium. We have previously reported that AIP1 functions as an endogenous inhibitor in pathological angiogenesis by blocking VEGFR-2 activity. Surprisingly, here we observe that mice with a global deletion of AIP1-knockout mice (AIP1-KO) exhibit reduced retinal angiogenesis with less sprouting and fewer branches. Vascular endothelial cell (but not neuronal)-specific deletion of AIP1 causes similar defects in retinal angiogenesis. The reduced retinal angiogenesis correlates with reduced expression in VEGFR-3 despite increased VEGFR-2 levels in AIP1-KO retinas. Consistent with the reduced expression of VEGFR-3, AIP1-KO show delayed developmental lymphangiogenesis in neonatal skin and mesentery, and mount weaker VEGF-C-induced cornea lymphangiogenesis. In vitro, human lymphatic endothelial cells with AIP1 small interfering RNA knockdown, retinal endothelial cells, and lymphatic endothelial cells isolated from AIP1-KO all show attenuated VEGF-C-induced VEGFR-3 signaling. Mechanistically, we demonstrate that AIP1 via vegfr-3-specific miR-1236 increases VEGFR-3 protein expression and that, by directly binding to VEGFR-3, it enhances VEGFR-3 endocytosis and stability.


Our in vivo and in vitro results provide the first insight into the mechanism by which AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic signaling.


DAB2IP protein, human; lymphangiogenesis; vascular endothelial growth factor A; vascular endothelial growth factor receptor-2; vascular endothelial growth factor receptor-3

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