Smooth muscle Notch1 mediates neointimal formation after vascular injury.
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.


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.
Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
Yuxin
Y
Li
Kyosuke
K
Takeshita
Ping-Yen
PY
Liu
Minoru
M
Satoh
Naotsugu
N
Oyama
Yasushi
Y
Mukai
Michael T
MT
Chin
Luke
L
Krebs
Michael I
MI
Kotlikoff
Freddy
F
Radtke
Thomas
T
Gridley
James K
JK
Liao
D000818:Animals; D001011:Aorta / Q000166:cytology; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000502:physiology*; D001808:Blood Vessels / Q000293:injuries*; D002339:Carotid Arteries; D049109:Cell Proliferation; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D051881:Receptor, Notch1 / Q000172:deficiency / Q000502:physiology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency; D012097:Repressor Proteins / Q000502:physiology*; D017539:Tunica Intima / Q000254:growth & development*
D051792:Basic Helix-Loop-Helix Proteins; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D012097:Repressor Proteins; C485778:Hey2 protein, mouse; C499373:Notch3 protein, mouse