TY - JOUR
T1 - Temporal-specific roles of Rac1 during vascular development and retinal angiogenesis
AU - Nohata, Nijiro
AU - Uchida, Yutaka
AU - Stratman, Amber N.
AU - Adams, Ralf H.
AU - Zheng, Yi
AU - Weinstein, Brant M.
AU - Mukouyama, Yoh Suke
AU - Gutkind, J. Silvio
N1 - Funding Information:
This work was partially supported by the Intramural Research Program of the National Institutes of Health , National Institute of Dental and Craniofacial Research (Project Z01DE000558) , and by funds provided by the UC San Diego Moores Cancer Center and Office of the Dean, Medical School, UC San Diego .
Publisher Copyright:
© 2016.
PY - 2016/3/15
Y1 - 2016/3/15
N2 - 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 anti-angiogeneic therapeutic targets for the treatment of many human diseases that involve aberrant neovascularization and blood vessel overgrowth.
AB - 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 anti-angiogeneic therapeutic targets for the treatment of many human diseases that involve aberrant neovascularization and blood vessel overgrowth.
KW - Angiogenesis
KW - Conditional gene knockout mouse
KW - In vitro three dimensional collagen matrix model
KW - Rac1
UR - http://www.scopus.com/inward/record.url?scp=84959513501&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2016.02.005
DO - 10.1016/j.ydbio.2016.02.005
M3 - Article
C2 - 26872874
AN - SCOPUS:84959513501
SN - 0012-1606
VL - 411
SP - 183
EP - 194
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -