We have identified the IFITM family of transmembrane proteins as important regulators of endothelial cell (EC) sprouting in vitro, and angiogenesis in vivo. During angiogenesis EC shift from quiescent cells in the walls of mature vessels, to migrating and proliferating cells as part of a sprout, to cells capable of generating lumens and forming anastomoses, and back to quiescent cells as the new vessel stabilizes. In the previous round of funding we identified a role for the notch signaling pathway in suppressing proliferation and branching at the tips of new capillary sprouts, work that has now been corroborated in several different labs. In this competing renewal we present data showing that in human the IFITM family of proteins are constitutively expressed in the vasculature and that they are expressed reciprocally in developing sprouts - IFITM1 in tip cells and IFITM2 in trunk cells. Both misexpression and knockdown of IFITMs disrupts sprouting and lumen formation in vitro and angiogenesis in vivo, and both block proliferation by inducing p21 expression. IFITM2, but not IFITM1, synergizes with notch signaling. The hypothesis we will test in this competing renewal is that the regulated expression by EC of the IFITM family of proteins is critical to the proper formation of lumenized vascular sprouts. We will use a combination of in vitro and in vivo approaches to test this hypothesis and to further our understanding of the role of this family in angiogenesis. Specifically, we will address the following three aims: 1. Determine the role of the IFITMs in endothelial sprouting and tube formation 2. Determine the mechanism(s) of IFITM signaling in endothelial cells 3. Identify the critical domains of IFITM1 and IFITM2 and their interacting partners

Public Health Relevance

We are interested in how the growth of new blood vessels is controlled as this process is critical in development, wound healing and cancer. We have identified a family of molecules called IFITM1-3, which are expressed by endothelial cells - the cells that line blood vessels - and which regulate many of the functions of these cells. In this project we will learn more about how these molecules work in the hope that we may manipulate them in the future to control blood vessel development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060067-12
Application #
8432818
Study Section
Special Emphasis Panel (ZRG1-CVRS-L (02))
Program Officer
Gao, Yunling
Project Start
1999-04-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
12
Fiscal Year
2013
Total Cost
$324,449
Indirect Cost
$112,391
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Ziegler, Mary E; Hatch, Michaela M S; Wu, Nan et al. (2016) mTORC2 mediates CXCL12-induced angiogenesis. Angiogenesis 19:359-71
Welch-Reardon, Katrina M; Wu, Nan; Hughes, Christopher C W (2015) A role for partial endothelial-mesenchymal transitions in angiogenesis? Arterioscler Thromb Vasc Biol 35:303-8
Spencer, K H; Kim, M Y; Hughes, C C W et al. (2014) A screen for short-range paracrine interactions. Integr Biol (Camb) 6:382-7
Ehsan, Seema M; Welch-Reardon, Katrina M; Waterman, Marian L et al. (2014) A three-dimensional in vitro model of tumor cell intravasation. Integr Biol (Camb) 6:603-10
Welch-Reardon, Katrina M; Ehsan, Seema M; Wang, Kehui et al. (2014) Angiogenic sprouting is regulated by endothelial cell expression of Slug. J Cell Sci 127:2017-28
Popson, Stephanie A; Ziegler, Mary E; Chen, Xiaofang et al. (2014) Interferon-induced transmembrane protein 1 regulates endothelial lumen formation during angiogenesis. Arterioscler Thromb Vasc Biol 34:1011-9
Newman, Andrew C; Chou, Wayne; Welch-Reardon, Katrina M et al. (2013) Analysis of stromal cell secretomes reveals a critical role for stromal cell-derived hepatocyte growth factor and fibronectin in angiogenesis. Arterioscler Thromb Vasc Biol 33:513-22
Newman, Andrew C; Hughes, Christopher C W (2012) Macrophages and angiogenesis: a role for Wnt signaling. Vasc Cell 4:13
Kim, Jai-Hyun; Peacock, Matthew R; George, Steven C et al. (2012) BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II. Angiogenesis 15:497-509
Newman, Andrew C; Nakatsu, Martin N; Chou, Wayne et al. (2011) The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol Biol Cell 22:3791-800

Showing the most recent 10 out of 24 publications