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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents

ID: 732118.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
Temporal-specific roles of Rac1 during vascular development and retinal angiogenesis
Authors:Nohata, N.; Uchida, Y.; Stratman, A. N.; Adams, R. H.; Zheng, Y.; Weinstein, B. M.; Mukouyama, Y. S.; Gutkind, J. S.
Date of Publication (YYYY-MM-DD):2016-03
Title of Journal:Dev Biol
Issue / Number:2
Start Page:183
End Page:194
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Angiogenesis, the formation of new blood vessels by remodeling and growth of pre-existing vessels, is a highly orchestrated process that requires a tight balance between pro-angiogenic and anti-angiogenic factors and the integration of their corresponding signaling networks. The family of Rho GTPases, including RhoA, Rac1, and Cdc42, play a central role in many cell biological processes that involve cytoskeletal changes and cell movement. Specifically for Rac1, we have shown that excision of Rac1 using a Tie2-Cre animal line results in embryonic lethality in midgestation (embryonic day (E) 9.5), with multiple vascular defects. However, Tie2-Cre can be also expressed during vasculogenesis, prior to angiogenesis, and is active in some hematopoietic precursors that can affect vessel formation. To circumvent these limitations, we have now conditionally deleted Rac1 in a temporally controlled and endothelial-restricted fashion using Cdh5(PAC)-iCreERT2 transgenic mice. In this highly controlled experimental in vivo system, we now show that Rac1 is required for embryonic vascular integrity and angiogenesis, and for the formation of superficial and deep vascular networks in the post-natal developing retina, the latter involving a novel specific function for Rac1 in vertical blood vessel sprouting. Aligned with these findings, we show that RAC1 is spatially involved in endothelial cell migration, invasion, and radial sprouting activities in 3D collagen matrix in vitro models. Hence, Rac1 and its downstream molecules may represent potential antiangiogeneic therapeutic targets for the treatment of many human diseases that involve aberrant neovascularization and blood vessel overgrowth. (C) 2016 Published by Elsevier Inc.
Free Keywords:Rac1; Angiogenesis; Conditional gene knockout mouse; In vitro three; dimensional collagen matrix model; endothelial-cells; mouse retina; ve-cadherin; rho-gtpases; cardiovascular development; sphingosine kinase-1; in-vitro; protein; permeability; sphingosine-1-phosphate; Developmental Biology
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Gutkind, JS (reprint author), Univ Calif San Diego, Moores Canc Ctr, 3855 Hlth Sci Dr 0803, La Jolla, CA 92093 USA. sgutkind@ucsd.edu %G English
Identifiers:ISSN:0012-1606 %R 10.1016/j.ydbio.2016.02.005 [ID No:1]
URL:<Go to ISI>://WOS:000372383500003 [ID No:2]
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