Published online before print May 29, 2003, doi: 10.1161/01.RES.0000079310.81429.C8
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Submitted on March 12, 2003
Revised on May 2, 2003
Accepted on May 19, 2003
EphA4-Mediated Rho Activation via Vsm-RhoGEF Expressed Specifically in Vascular Smooth Muscle Cells
Hisakazu Ogita ;
From the Department of Structural Analysis (H.O., S.K., Y.K., M.M., N.M.), National Cardiovascular Center Research Institute, Suita, Osaka, Japan; the Department of Molecular and Cellular Pathology (H.S.), Hokkaido University, Sapporo, Japan.
* To whom correspondence should be addressed. E-mail: nmochizu{at}ri.ncvc.go.jp.
Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein-coupled receptors. In the present study, we demonstrate a novel cell-cell interaction-mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and further studied the molecular mechanism of Vsm-RhoGEF regulation by EphA4. Immunohistochemical analysis showed that EphA4 and Vsm-RhoGEF expression overlapped in VSMCs. Additionally, tyrosine phosphorylation of Vsm-RhoGEF induced by EphA4 upon ephrin-A1 stimulation enhanced the Vsm-RhoGEF activity for RhoA. The requirement of Vsm-RhoGEF for ephrin-A1-induced assembly of actin stress fibers in VSMCs was shown by the overexpression of a dominant-negative form of VSM-RhoGEF and by the depletion of Vsm-RhoGEF using RNA interference. These results suggested that ephrin-A1-triggered EphA4-Vsm-RhoGEF-RhoA pathway is involved in the cell-cell interaction-mediated RhoA activation that regulates vascular smooth muscle contractility.
Key words: smooth muscle cells • Rho • Eph • ephrin • contraction
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