Published online before print March 7, 2002, doi: 10.1161/01.RES.0000014823.75393.4D
© 2002 American Heart Association, Inc.
Cellular Biology |
Autocrine Regulation of Myocyte Cx43 Expression by VEGF
From the Departments of Medicine and Pathology and Immunology, and the Center for Cardiovascular Research (R.C.P., K.A.Y., J.E.S.), Washington University School of Medicine, St Louis, Mo; and the Physiology Institute (A.G.K.), University of Bern, Bern, Switzerland.
Correspondence to Jeffrey E. Saffitz, MD, PhD, Dept of Pathology, Box 8118, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail saffitz{at}pathology.wustl.edu
Cardiac myocytes can rapidly adjust their expression of gap junction channel proteins in response to changes in load. Previously, we showed that after only 1 hour of linear pulsatile stretch (110% of resting cell length; 3 Hz), expression of connexin43 (Cx43) by cultured neonatal rat ventricular myocytes is increased by 
2-fold and impulse propagation is significantly more rapid. In the present study, we tested the hypothesis that vascular endothelial growth factor (VEGF), acting downstream of transforming growth factor-ß (TGF-ß), mediates stretch-induced upregulation of Cx43 expression by cardiac myocytes. Incubation of nonstretched cells with exogenous VEGF (100 ng/mL) or TGF-ß (10 ng/mL) for 1 hour increased Cx43 expression by 1.8-fold, comparable to that observed in cells subjected to pulsatile stretch for 1 hour. Stretch-induced upregulation of Cx43 expression was blocked by either anti-VEGF antibody or anti-TGF-ß antibody. Stretch-induced enhancement of conduction was also blocked by anti-VEGF antibody. ELISA assay showed that VEGF was secreted into the culture medium during stretch. Furthermore, stretch-conditioned medium stimulated Cx43 expression in nonstretched cells. This effect was also blocked by anti-VEGF antibody. Upregulation of Cx43 expression stimulated by exogenous TGF-ß was blocked by anti-VEGF antibody, but VEGF-stimulation of Cx43 expression was not blocked by anti-TGF-ß antibody. Thus, stretch-induced upregulation of Cx43 expression is mediated, at least in part, by VEGF, which acts downstream of TGF-ß. Because the cultures contained only 5% nonmyocytic cells, these results indicate that myocyte-derived VEGF, secreted in response to stretch, acts in an autocrine fashion to enhance intercellular coupling.
Key Words: connexin43 • gap junctions • vascular endothelial growth factor • transforming growth factor-&bgr • pulsatile stretch
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