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

Huanjiao Jenny Zhou, Xiaodong Chen, Qunhua Huang, Renjing Liu, Haifeng Zhang, Yingdi Wang, Yu Jin, Xiaoling Liang, Lin Lu, Zhe Xu, Wang Min

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

OBJECTIVE - : 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. APPROACH AND RESULTS - : 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. CONCLUSION - : 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.

Original languageEnglish (US)
Pages (from-to)603-615
Number of pages13
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number3
DOIs
StatePublished - Mar 1 2014

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Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor
Proteins
Lymphangiogenesis
Endothelial Cells
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor Receptor-2
Pathologic Neovascularization
Mesentery
Vascular Endothelium
Endocytosis
Knockout Mice

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses. / Zhou, Huanjiao Jenny; Chen, Xiaodong; Huang, Qunhua; Liu, Renjing; Zhang, Haifeng; Wang, Yingdi; Jin, Yu; Liang, Xiaoling; Lu, Lin; Xu, Zhe; Min, Wang.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 34, No. 3, 01.03.2014, p. 603-615.

Research output: Contribution to journalArticle

Zhou, Huanjiao Jenny ; Chen, Xiaodong ; Huang, Qunhua ; Liu, Renjing ; Zhang, Haifeng ; Wang, Yingdi ; Jin, Yu ; Liang, Xiaoling ; Lu, Lin ; Xu, Zhe ; Min, Wang. / AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses. In: Arteriosclerosis, thrombosis, and vascular biology. 2014 ; Vol. 34, No. 3. pp. 603-615.
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T1 - AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses

AU - Zhou, Huanjiao Jenny

AU - Chen, Xiaodong

AU - Huang, Qunhua

AU - Liu, Renjing

AU - Zhang, Haifeng

AU - Wang, Yingdi

AU - Jin, Yu

AU - Liang, Xiaoling

AU - Lu, Lin

AU - Xu, Zhe

AU - Min, Wang

PY - 2014/3/1

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N2 - OBJECTIVE - : 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. APPROACH AND RESULTS - : 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. CONCLUSION - : 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.

AB - OBJECTIVE - : 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. APPROACH AND RESULTS - : 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. CONCLUSION - : 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.

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