on September 24, 2009
Published online before print September 24, 2009, doi: 10.1161/ATVBAHA.109.195305
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 27, 2009
Accepted on August 31, 2009
Actin-Binding Rho Activating Protein (Abra) Is Essential for Fluid Shear Stress–Induced Arteriogenesis
Kerstin Troidl *;
From the Max-Planck-Institute for Heart and Lung Research (K.T., I.R., Y.M., L.G., I.P., H.A., W.S., W.S., C.T.), Bad Nauheim, Germany; the Department of Anatomy (W.-J.C.), Xiangsha School of Medicine, Central South University, Changsha, Hunan, China; the VU University Medical Center (O.L.V., A.J.H.), Amsterdam, The Netherlands; the Division of Vascular and Endovascular Surgery (K.T., H.A., T.S.-R.), Goethe-University of Frankfurt/Main, Germany; and Cardiology and Angiology (K.G.), Med. Hochschule Hannover, Germany.
* To whom correspondence should be addressed. E-mail: kerstin.troidl{at}mpi-bn.mpg.de.
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.
Methods and 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.
Key words: arteriogenesis • Abra • fluid shear stress • smooth muscle cells • proliferation