Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation

被引：14

作者：

Chang, Kyung Hee ^{[1
,2
]}

Nayak, Ramesh C. ^{[2
]}

Roy, Swarnava ^{[2
]}

Perumbeti, Ajay ^{[1
]}

Wellendorf, Ashley M. ^{[2
]}

Bezold, Katie Y. ^{[2
]}

Pirman, Megan ^{[1
]}

Hill, Sarah E. ^{[1
]}

Starnes, Joseph ^{[2
]}

Loberg, Anastacia ^{[2
]}

Zhou, Xuan ^{[2
]}

Inagami, Tadashi ^{[3
]}

Zheng, Yi ^{[2
]}

Malik, Punam ^{[2
]}

Cancelas, Jose A. ^{[1
,2
]}

机构：

[1] Univ Cincinnati, Coll Med, Hoxworth Blood Ctr, Cincinnati, OH 45267 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Cell Biol, Cincinnati, OH 45229 USA

[3] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

美国国家卫生研究院;

关键词：

SICKLE-CELL-DISEASE; ANGIOTENSIN-II; BONE-MARROW; BLOOD-PRESSURE; PROGENITOR CELLS; TYPE-2; RECEPTOR; NITRIC-OXIDE; RANDOMIZED-TRIAL; HEART-FAILURE; IN-VIVO;

D O I：

10.1038/ncomms6914

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Patients with organ failure of vascular origin have increased circulating haematopoietic stem cells and progenitors (HSC/P). Plasma levels of angiotensin II (Ang-II), are commonly increased in vasculopathies. Hyperangiotensinemia results in activation of a very distinct Ang-II receptor set, Rho family GTPase members, and actin in bone marrow endothelial cells (BMEC) and HSC/P, which results in decreased membrane integrin activation in both BMEC and HSC/P, and in HSC/P de-adhesion and mobilization. The Ang-II effect can be reversed pharmacologically and genetically by inhibiting Ang-II production or signalling through BMEC AT(2)R, HSCP Ang-II receptor type 1 (AT(1)R)/AT(2)R or HSC/P RhoA, but not by interfering with other vascular tone mediators. Hyperangiotensinemia and high counts of circulating HSC/P seen in sickle cell disease (SCD) as a result of vascular damage, is significantly decreased by Ang-II inhibitors. Our data define for the first time the role of Ang-II HSC/P traffic regulation and redefine the haematopoietic consequences of anti-angiotensin therapy in SCD.

引用

页数：11