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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2093.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Actin-Binding Rho Activating Protein (Abra) Is Essential for Fluid Shear Stress-Induced Arteriogenesis

Kerstin Troidl; Inka Rüding; Wei-Jun Cai; Yvonne Mücke; Leonie Grossekettler; Izabela Piotrowska; Hanna Apfelbeck; Wilma Schierling; Oscar L. Volger; Anton J. Horrevoets; Karsten Grote; Thomas Schmitz-Rixen; Wolfgang Schaper; Christian 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. Current affiliation for I.P.: Molecular Haematology and Cancer Biology, London, UK. Current address for W.S.: Regensburg, Germany.

Correspondence to Kerstin Troidl, Max-Planck-Institute for Heart and Lung Research, Parkstr. 1, D-61231 Bad Nauheim, Germany. 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.

In a rat model of chronically elevated fluid shear stress we show that Actin-binding Rho activating protein (Abra) is upregulated in growing collaterals and serves as an inducer of arteriogenesis. Our results indicate that 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