Arteriogenesis is critical not only for forming new arterial vessels in development but also for increasing arterial blood supply to the ischemic tissues associated with various vascular diseases. New arteries in adult circulation can be formed either by expansion of the pre-existing arterial vessels or by de novo arteriogenesis. Two major triggers of arteriogenesis are VEGFR2 stimulation and shear stress (SS). Both VEGFR2 stimulation and SS activate multiple signaling cascades including the PI3K-Akt/eN0S pathway and the Raf/MEK/Erk1/2 MAPK pathway. However, the precise molecular mechanisms that govern the action of these signaling pathways in arteriogenesis remain elusive. Our laboratory was one of the first labs that discovered Sin1, an essential adaptor molecule for the integrity and activity of mammalian target of rapamycin (mTOR) complex 2 (mT0RC2). Importantly, we demonstrated that Sin1 plays a crucial role in mediating PI3K signal and for Akt activation. In addition, we also demonstrated that Sin1 is involved in regulating the MAPK pathways. These results thus suggest that Sin1 should be an important player in VEGF and SS signaling. Indeed, our preliminary study demonstrated that Sin1 deletion in mice results in severe defects in generating mature blood vessels and irregulariy formed dorsal aorta. Because Sin1 is capable of regulating not only the Aktl signaling pathway (via mT0RC2) but also the MAPK pathway, we hypothesize that its deficiency may perturb the balance of the Akt and Raf1-ERK1/2 activities, thus affecting arterial blood vessel development. This project will establish a highly collaborative program with other laboratories in this PPG to investigate how Sin1 may coordinate VEGF-dependent Raf/Erk1/2 (Project 1) and Akt/eNOS (Project 2) signaling pathways at the molecular level and develop mouse models to study Sinl's roles in arteriogenesis. In addition, the role of Sin1 in arteriogenesis in response to shear stress (Project 4) will also be investigated. The following three Specific Aims will be pursued: 1) To investigate the regulation of Sin1 in endothelial cells;2) To determine the mTOR dependent and independent role of Sin1 in arterial marker gene expression;3) To investigate the in vivo role of Sin1 in arteriogenesis.

Public Health Relevance

; Arteriogenesis is highly important for patients with occlusive vascular diseases such as atherosclerosis to develop new blood supply that bypass areas of arterial obstructions. Sin1 is an adaptor molecule that controls at least two intracellular signaling pathways in arteriogenesis. Our project is to understand the function and regulation of Sin1 in arteriogenesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Yale University
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