Angiogenesis, the process of new blood vessel formation, is involved in many physiological and pathological settings such as ischemia, diabetes, atherosclerosis and cancer. Several angiogenic pathways have been identified to be essential for developmental angiogenesis and vascular adaptive responses in adult. It has been recognized that certain genes that play important roles in pathological (e.g, inflammation and ischemia) are not involved in physiological angiogenesis. However, the underlining mechanisms for the pathogenesis-associated angiogenesis are not well understood. We hypothesize that pathological angiogenesis-associated genes are expressed, activated or associated with potent angiogenic pathways in response to pathological stimuli where they modulate postnatal angiogenic responses and tissue remodeling. We have identified AIP1, a novel signaling protein as a potent inhibitor in pathological but not developmental angiogenesis. In this application we propose the following specific aims to define the role of AIP1 in inflammatory angiogenesis: 1) Define the mechanism by which AIP1 inhibits VEGFR2 signaling. We will examine if AIP1 binds to an active form of VEGFR2, delaying VEGFR2 endocytosis and/or assisting recruitment of phosphatase(s) to VEGFR2 to attenuate VEGFR2-dependent angiogenic signaling. 2) Determine how AIP1 inhibits NF-kB-dependent inflammation, and the regulation of AIP1 expression in pathological angiogenesis. We will determine how AIP1 via its C-terminal CC/LZ domain competes with NEMO for the RIP1 association, disrupting IKK complex formation, and how JAK2/Bmx-SOCS3 mediates AIP1 phosphorylation and degradation during pathological angiogenesis. 3) Define the EC-specific functions of AIP1 in inflammation-induced angiogenesis. We will determine inflammatory responses and pathological angiogenesis in mouse models using EC-specific AIP1- KO mice and EC-specific AIP1 transgenic mice. We will test the potential therapeutic effects of AIP1-derived peptides in these models.

Public Health Relevance

The mechanism for genes involved in new blood vessel formation during pathogenesis is not well understood. This revised application will provide mechanistic insights on the role of AIP1 in both inflammation and pathological angiogenesis, and facilitate the development of potential new therapeutic approaches to treat angiogenesis-dependent cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL115148-02
Application #
8706216
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2013-08-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
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Huang, Qunhua; Zhou, Huanjiao Jenny; Zhang, Haifeng et al. (2015) Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function. Circulation 131:1082-97
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Zhou, Huanjiao Jenny; Chen, Xiaodong; Huang, Qunhua et al. (2014) AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses. Arterioscler Thromb Vasc Biol 34:603-15

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