Smooth muscle notch1 mediates neointimal formation after vascular injury

Yuxin Li, Kyosuke Takeshita, Ping-Yen Liu, Minoru Satoh, Naotsugu Oyama, Yasushi Mukai, Michael T. Chin, Luke Krebs, Michael I. Kotlikoff, Freddy Radtke, Thomas Gridley, James K. Liao

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

BACKGROUND-: Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. METHODS AND RESULTS-: We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1), SMC-specific Notch1 heterozygous deficient (smN1), and general Notch3 homozygous deficient (N3) mice. Compared with wild-type or control mice, N1 and smN1 mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3 mice. Indeed, SMCs derived from explanted aortas of either N1- or smN1 mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3 mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1- or smN1 mice. In SMCs derived from CHF1/Hey2 mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. CONCLUSIONS-: These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.

Original languageEnglish
Pages (from-to)2686-2692
Number of pages7
JournalCirculation
Volume119
Issue number20
DOIs
Publication statusPublished - 2009 May 26

Fingerprint

Vascular System Injuries
Smooth Muscle Myocytes
Smooth Muscle
Carotid Arteries
Ligation
Cell Proliferation
Staining and Labeling
Proliferating Cell Nuclear Antigen
Chemotaxis
Vascular Diseases
Vascular Smooth Muscle
Caspase 3
Cell Movement
Aorta
Apoptosis

All Science Journal Classification (ASJC) codes

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Li, Y., Takeshita, K., Liu, P-Y., Satoh, M., Oyama, N., Mukai, Y., ... Liao, J. K. (2009). Smooth muscle notch1 mediates neointimal formation after vascular injury. Circulation, 119(20), 2686-2692. https://doi.org/10.1161/CIRCULATIONAHA.108.790485
Li, Yuxin ; Takeshita, Kyosuke ; Liu, Ping-Yen ; Satoh, Minoru ; Oyama, Naotsugu ; Mukai, Yasushi ; Chin, Michael T. ; Krebs, Luke ; Kotlikoff, Michael I. ; Radtke, Freddy ; Gridley, Thomas ; Liao, James K. / Smooth muscle notch1 mediates neointimal formation after vascular injury. In: Circulation. 2009 ; Vol. 119, No. 20. pp. 2686-2692.
@article{a11a49a6f9804fccaef97b2344c535e2,
title = "Smooth muscle notch1 mediates neointimal formation after vascular injury",
abstract = "BACKGROUND-: Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. METHODS AND RESULTS-: We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1), SMC-specific Notch1 heterozygous deficient (smN1), and general Notch3 homozygous deficient (N3) mice. Compared with wild-type or control mice, N1 and smN1 mice showed a 70{\%} decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3 mice. Indeed, SMCs derived from explanted aortas of either N1- or smN1 mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3 mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1- or smN1 mice. In SMCs derived from CHF1/Hey2 mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. CONCLUSIONS-: These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.",
author = "Yuxin Li and Kyosuke Takeshita and Ping-Yen Liu and Minoru Satoh and Naotsugu Oyama and Yasushi Mukai and Chin, {Michael T.} and Luke Krebs and Kotlikoff, {Michael I.} and Freddy Radtke and Thomas Gridley and Liao, {James K.}",
year = "2009",
month = "5",
day = "26",
doi = "10.1161/CIRCULATIONAHA.108.790485",
language = "English",
volume = "119",
pages = "2686--2692",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "20",

}

Li, Y, Takeshita, K, Liu, P-Y, Satoh, M, Oyama, N, Mukai, Y, Chin, MT, Krebs, L, Kotlikoff, MI, Radtke, F, Gridley, T & Liao, JK 2009, 'Smooth muscle notch1 mediates neointimal formation after vascular injury', Circulation, vol. 119, no. 20, pp. 2686-2692. https://doi.org/10.1161/CIRCULATIONAHA.108.790485

Smooth muscle notch1 mediates neointimal formation after vascular injury. / Li, Yuxin; Takeshita, Kyosuke; Liu, Ping-Yen; Satoh, Minoru; Oyama, Naotsugu; Mukai, Yasushi; Chin, Michael T.; Krebs, Luke; Kotlikoff, Michael I.; Radtke, Freddy; Gridley, Thomas; Liao, James K.

In: Circulation, Vol. 119, No. 20, 26.05.2009, p. 2686-2692.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Smooth muscle notch1 mediates neointimal formation after vascular injury

AU - Li, Yuxin

AU - Takeshita, Kyosuke

AU - Liu, Ping-Yen

AU - Satoh, Minoru

AU - Oyama, Naotsugu

AU - Mukai, Yasushi

AU - Chin, Michael T.

AU - Krebs, Luke

AU - Kotlikoff, Michael I.

AU - Radtke, Freddy

AU - Gridley, Thomas

AU - Liao, James K.

PY - 2009/5/26

Y1 - 2009/5/26

N2 - BACKGROUND-: Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. METHODS AND RESULTS-: We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1), SMC-specific Notch1 heterozygous deficient (smN1), and general Notch3 homozygous deficient (N3) mice. Compared with wild-type or control mice, N1 and smN1 mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3 mice. Indeed, SMCs derived from explanted aortas of either N1- or smN1 mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3 mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1- or smN1 mice. In SMCs derived from CHF1/Hey2 mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. CONCLUSIONS-: These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.

AB - BACKGROUND-: Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. METHODS AND RESULTS-: We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1), SMC-specific Notch1 heterozygous deficient (smN1), and general Notch3 homozygous deficient (N3) mice. Compared with wild-type or control mice, N1 and smN1 mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3 mice. Indeed, SMCs derived from explanted aortas of either N1- or smN1 mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3 mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1- or smN1 mice. In SMCs derived from CHF1/Hey2 mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. CONCLUSIONS-: These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.

UR - http://www.scopus.com/inward/record.url?scp=67249123141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67249123141&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.108.790485

DO - 10.1161/CIRCULATIONAHA.108.790485

M3 - Article

VL - 119

SP - 2686

EP - 2692

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 20

ER -