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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1112.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Sonic Hedgehog Induces Notch Target Gene Expression in Vascular Smooth Muscle Cells via VEGF-A

David Morrow; John P. Cullen; Weimin Liu; Shaunta Guha; Catherine Sweeney; Yvonne A. Birney; Nora Collins; Dermot Walls; Eileen M. Redmond; Paul A. Cahill

From the Vascular Health Research Centre, Faculty of Science and Health (S.G., C.S., Y.A.B., N.C., P.A.C.), Dublin City University, Ireland; the Department of Surgery (D.M., J.P.C., W.L., E.M.R.), University of Rochester Medical Center, NY; and the School of Biotechnology and the National Centre for Sensor Research (D.W.), Dublin City University, Ireland.

Correspondence to Paul A. Cahill, Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland. E-mail paul.cahill{at}dcu.ie

Objective— Notch, VEGF, and components of the Hedgehog (Hh) signaling pathway have been implicated in vascular morphogenesis. The role of Notch in mediating hedgehog control of adult vascular smooth muscle cell (SMC) growth and survival remains unexplored.

Methods and Results— In cultured SMCs, activation of Hh signaling with recombinant rShh (3.5 µg/mL) or plasmid encoded Shh increased Ptc1 expression, enhanced SMC growth and survival and promoted Hairy-related transcription factor (Hrt) expression while concomitantly increasing VEGF-A levels. These effects were significantly reversed after Hh inhibition with cyclopamine. Shh-induced stimulation of Hrt-3 mRNA and SMC growth and survival was attenuated after inhibition of Notch-mediated CBF-1/RBP-Jk-dependent signaling with RPMS-1 while siRNA knockdown of Hrt-3 inhibited SMC growth and survival. Recombinant VEGF-A increased Hrt-3 mRNA levels while siRNA knockdown abolished rShh stimulated VEGF-A expression while concomitantly inhibiting Shh-induced increases in Hrt-3 mRNA levels, proliferating cell nuclear antigen (PCNA), and Notch 1 IC expression, respectively. Hedgehog components were expressed within intimal SMCs of murine carotid arteries after vascular injury concomitant with a significant increase in mRNA for Ptc1, Gli₂, VEGF-A, Notch 1, and Hrts.

Conclusion— Hedgehog promotes a coordinate regulation of Notch target genes in adult SMCs via VEGF-A.

Notch, VEGF-A, and Hedgehogs (Hh) have been implicated in vascular morphogenesis and modeling of the embryonic vasculature. The current study demonstrated that Hh components specifically coordinate Notch signaling through VEGF-A activation in vascular SMCs in vitro and further that these component pathways are recapitulated within intimal cells after injury in vivo.

Key Words: Hedgehog • notch • apoptosis • proliferation • vascular smooth muscle • VEGF • vascular remodeling