Actin-binding rho activating protein (Abra) is essential for fluid shear stress-induced arteriogenesis.
OBJECTIVE
Arteriogenesis, the development of a collateral circulation, is important for tissue survival but remains functionally defective because of early normalization of fluid shear stress (FSS). Using a surgical model of chronically elevated FSS we showed that rabbits exhibited normal blood flow reserve after femoral artery ligature (FAL). Inhibition of the Rho pathway by Fasudil completely blocked the beneficial effect of FSS. In a genome-wide gene profiling we identified actin-binding Rho activating protein (Abra), which was highly upregulated in growing collaterals.


RESULTS
qRT-PCR and Western blot confirmed highly increased FSS-dependent expression of Abra in growing collaterals. NO blockage by L-NAME abolished FSS-generated Abra expression as well as the whole arteriogenic process. Cell culture studies demonstrated an Abra-triggered proliferation of smooth muscle cells through a mechanism that requires Rho signaling. Local intracollateral adenoviral overexpression of Abra improved collateral conductance by 60% in rabbits compared to the natural response after FAL. In contrast, targeted deletion of Abra in CL57BL/6 mice led to impaired arteriogenesis.


CONCLUSIONS
FSS-induced Abra expression during arteriogenesis is triggered by NO and leads to stimulation of collateral growth by smooth muscle cell proliferation.
Max-Planck-Institute for Heart and Lung Research, Parkstr. 1, D-61231 Bad Nauheim, Germany. kerstin.troidl@mpi-bn.mpg.de
Kerstin
K
Troidl
Inka
I
Rüding
Wei-Jun
WJ
Cai
Yvonne
Y
Mücke
Leonie
L
Grossekettler
Izabela
I
Piotrowska
Hanna
H
Apfelbeck
Wilma
W
Schierling
Oscar L
OL
Volger
Anton J
AJ
Horrevoets
Karsten
K
Grote
Thomas
T
Schmitz-Rixen
Wolfgang
W
Schaper
Christian
C
Troidl
D000199:Actins / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000254:growth & development* / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003097:Collateral Circulation / Q000502:physiology; D018014:Gene Transfer Techniques; D018056:Hemorheology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013552:Swine; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C518897:Abra protein, mouse; D000199:Actins; D008840:Microfilament Proteins; D020741:rho GTP-Binding Proteins