Published online before print September 2, 2004, doi: 10.1161/01.ATV.0000143936.77094.a4
© 2004 American Heart Association, Inc.
Vascular Biology |
Transcription Factor CHF1/Hey2 Regulates Neointimal Formation In Vivo and Vascular Smooth Muscle Proliferation and Migration In Vitro
From Vascular Medicine Research, Brigham & Women’s Hospital and Harvard Medical School, Cambridge, Mass.
Correspondence to Michael T. Chin, Vascular Medicine Research, Brigham and Women’s Hospital, 65 Landsdowne Street, Room 277, Cambridge, MA 02139. E-mail mchin{at}rics.bwh.harvard.edu
Objective— To determine the role of the cardiovascular-restricted, hairy-related bHLH transcription factor, CHF1/Hey2, in the biological response to vascular injury.
Methods and Results— We investigated the response of CHF1/Hey2-deficient mice to vascular injury in vivo and the response of primary cultured vascular smooth muscle cells (VSMCs) from these mice to growth factors in vitro. Neointima formation after arterial wire injury is decreased in knockout (KO) compared with wild-type (WT) mice (0.025±0.011 mm2 in WT [n=13]) versus 0.016±0.008 mm2 in KO (n=12; P<0.05) and is accompanied by reduced cellular proliferation. CHF1/Hey2-deficient VSMCs proliferate slowly compared with WT VSMCs and also show decreased migration in response to platelet-derived growth factor (PDGF) (62.6±10.3 CPF versus 37.2±13.5 CPF; P<0.01) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) (27.4±7.7 CPF versus 6.4±3.7 CPF, P<0.05). Furthermore, lamellipodia formation and membrane ruffling induced by these chemoattractants are diminished in KO VSMCs, which is correlated with decreased activation of the small GTPase Rac1. Although total Rac1 protein was not changed in KO VSMCs, the level of the Rac guanine exchange factor (GEF), Sos1, was decreased.
Conclusions— CHF1/Hey2 is an important regulator of vascular smooth muscle cell (VSMC) accumulation during vascular remodeling and responsiveness to growth factors in vitro.
CHF1/Hey2-deficient mice show decreased neointima formation after vascular injury. VSMCs from these mice show decreased proliferation, migration, cytoskeletal rearrangement, activation of the small GTPase Rac1, and expression of the Rac guanine exchange factor (GEF), Sos1. CHF1/Hey2 is an important regulator of vascular remodeling and growth factor responsiveness in VSMCs.
Key Words: genetically altered mice • growth factors • vascular biology • vascular muscle
This article has been cited by other articles:
 |
|
 |
|
  N. Sawada, H. Itoh, K. Miyashita, H. Tsujimoto, M. Sone, K. Yamahara, Z. P. Arany, F. Hofmann, and K. Nakao Cyclic GMP Kinase and RhoA Ser188 Phosphorylation Integrate Pro- and Antifibrotic Signals in Blood Vessels Mol. Cell. Biol., November 15, 2009; 29(22): 6018 - 6032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, K. Takeshita, P.-Y. Liu, M. Satoh, N. Oyama, Y. Mukai, M. T. Chin, L. Krebs, M. I. Kotlikoff, F. Radtke, et al. Smooth Muscle Notch1 Mediates Neointimal Formation After Vascular Injury Circulation, May 26, 2009; 119(20): 2686 - 2692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Deaton, Q. Gan, and G. K. Owens Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1027 - H1037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Morrow, S. Guha, C. Sweeney, Y. Birney, T. Walshe, C. O'Brien, D. Walls, E. M. Redmond, and P. A. Cahill Notch and Vascular Smooth Muscle Cell Phenotype Circ. Res., December 5, 2008; 103(12): 1370 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. McCabe and M. Bronner-Fraser Essential role for PDGF signaling in ophthalmic trigeminal placode induction Development, May 15, 2008; 135(10): 1863 - 1874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tang, S. Urs, and L. Liaw Hairy-Related Transcription Factors Inhibit Notch-Induced Smooth Muscle {alpha}-Actin Expression by Interfering With Notch Intracellular Domain/CBF-1 Complex Interaction With the CBF-1-Binding Site Circ. Res., March 28, 2008; 102(6): 661 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tanaka, H. Sato, H. Doi, C. A. Yoshida, T. Shimizu, H. Matsui, M. Yamazaki, H. Akiyama, K. Kawai-Kowase, T. Iso, et al. Runx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells Mol. Cell. Biol., February 1, 2008; 28(3): 1147 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. Gerthoffer Migration of Airway Smooth Muscle Cells Proceedings of the ATS, January 1, 2008; 5(1): 97 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kaetsu, Y. Yamamoto, S. Sugihara, T. Matsuura, G. Igawa, K. Matsubara, O. Igawa, C. Shigemasa, and I. Hisatome Role of cysteinyl leukotrienes in the proliferation and the migration of murine vascular smooth muscle cells in vivo and in vitro Cardiovasc Res, October 1, 2007; 76(1): 160 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xie, M. C. Gong, W. Su, J. Turk, and Z. Guo Group VIA Phospholipase A2 (iPLA2beta) Participates in Angiotensin II-induced Transcriptional Up-regulation of Regulator of G-protein Signaling-2 in Vascular Smooth Muscle Cells J. Biol. Chem., August 31, 2007; 282(35): 25278 - 25289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Gridley Notch signaling in vascular development and physiology Development, August 1, 2007; 134(15): 2709 - 2718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fischer and M. Gessler Delta Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors Nucleic Acids Res., July 14, 2007; 35(14): 4583 - 4596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Shirvani, L. Mookanamparambil, M. F. Ramoni, and M. T. Chin Transcription factor CHF1/Hey2 regulates the global transcriptional response to platelet-derived growth factor in vascular smooth muscle cells Physiol Genomics, June 19, 2007; 30(1): 61 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Koibuchi and M. T. Chin CHF1/Hey2 Plays a Pivotal Role in Left Ventricular Maturation Through Suppression of Ectopic Atrial Gene Expression Circ. Res., March 30, 2007; 100(6): 850 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. T. Gerthoffer Mechanisms of Vascular Smooth Muscle Cell Migration Circ. Res., March 16, 2007; 100(5): 607 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kawai-Kowase and G. K. Owens Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 2007; 292(1): C59 - C69. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Xiang, Y. Sakata, L. Cui, J. M. Youngblood, H. Nakagami, J. K. Liao, R. Liao, and M. T. Chin Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1997 - H2006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wei, T. E. Gorman, X. Liu, B. Ith, A. Tseng, Z. Chen, D. I. Simon, M. D. Layne, and S.-F. Yet Increased Neointima Formation in Cysteine-Rich Protein 2-Deficient Mice in Response to Vascular Injury Circ. Res., December 9, 2005; 97(12): 1323 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Doi, T. Iso, M. Yamazaki, H. Akiyama, H. Kanai, H. Sato, K. Kawai-Kowase, T. Tanaka, T. Maeno, E.-i. Okamoto, et al. HERP1 Inhibits Myocardin-Induced Vascular Smooth Muscle Cell Differentiation by Interfering With SRF Binding to CArG Box Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2328 - 2334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fischer, J. Klattig, B. Kneitz, H. Diez, M. Maier, B. Holtmann, C. Englert, and M. Gessler Hey Basic Helix-Loop-Helix Transcription Factors Are Repressors of GATA4 and GATA6 and Restrict Expression of the GATA Target Gene ANF in Fetal Hearts Mol. Cell. Biol., October 15, 2005; 25(20): 8960 - 8970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Proweller, W. S. Pear, and M. S. Parmacek Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation J. Biol. Chem., March 11, 2005; 280(10): 8994 - 9004. [Abstract] [Full Text] [PDF]
|
|