Abstract 357: Critical Role of Vascular Smooth Muscle Notch1 in Mediating Neointimal Formation
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. Because Notch1 regulates cellular differentiation and proliferation, we hypothesize that Notch1 signaling in vascular smooth muscle cells (SMC) may contribute to neointimal formation following vascular injury. Here we show that Notch1 in SMC plays a critical role in mediating intimal proliferation.
Methods and Results: We performed carotid artery ligation in wild-type (WT), control (smMHC-Cre; smMHC-Cre recombinase transgenic mice), general Notch1 heterozygous deficient (N1+/−), and SMC-specific Notch1 heterozygous deficient (smN1+/−; Notch1flox/+, smMHC-Cre) mice. The expression of Notch1, but not Notch3, was upregulated in SMC of ligated arteries. Compared to WT or smMHC-Cre mice, both N1+/− and smN1+/− mice showed decreased neointimal formation (I/M ratio: WT vs. N1+/−, 1.36 ± 0.20 vs. 0.44 ± 0.05; smMHC-Cre vs. smN1+/−, 1.25 ± 0.12 vs. 0.45 ± 0.05: n=10 for each group, P<0.01). Indeed, SMC derived from explanted aortas of either N1+/− or smN1+/− mice demonstrated decreased chemotaxis compared to that of WT or control mice. Furthermore, SMC from either N1+/− or smN1+/− mice showed decreased SMC proliferation and increased apoptosis. This correlated with decreased staining of PCNA positive SMC in the neointima of ligated arteries of N1+/− or smN1+/− mice and increased staining of cleaved caspase 3 compared to that of WT or controlled mice.
Conclusion: These findings indicate that Notch1 in SMC plays an important role in regulating intimal formation following vascular injury and suggests that therapies, which target Notch 1 in SMC may be beneficial in SMC proliferative diseases such as restenosis, arteriosclerosis and transplant-associated arteriopathy.