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(Circulation Research. 2006;98:1468.)
© 2006 American Heart Association, Inc.

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Smooth Muscle -Actin Is a Direct Target of Notch/CSL

Michela Noseda, YangXin Fu, Kyle Niessen, Fred Wong, Linda Chang, Graeme McLean, Aly Karsan

From the Departments of Medical Biophysics (M.N., Y.F., K.N., F.W., L.C., G.M., A.K.) and Pathology and Laboratory Medicine (A.K.), British Columbia Cancer Agency, Vancouver; and Department of Pathology and Laboratory Medicine (M.N., Y.F., A.K.) and Experimental Medicine Program (K.N., L.C., G.M., A.K.), University of British Columbia, Vancouver, Canada.

Correspondence to Aly Karsan, British Columbia Cancer Research Centre, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3, Canada. E-mail akarsan{at}bccrc.ca

	Abstract

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Intercellular signaling mediated by Notch receptors is essential for proper cardiovascular development and homeostasis. Notch regulates cell fate decisions that affect proliferation, survival, and differentiation of endothelial and smooth muscle cells. It has been reported that Jagged1–Notch interactions may participate in endocardial cushion formation by inducing endothelial-to-mesenchymal transformation. Here, we show that Notch directly regulates expression of the mesenchymal and smooth muscle cell marker smooth muscle -actin (SMA) in endothelial and vascular smooth muscle cells via activation of its major effector, CSL. Notch/CSL activation induces SMA expression during endothelial-to-mesenchymal transformation, and Notch activation is required for expression of SMA in vascular smooth muscle cells. CSL directly binds a conserved cis element in the SMA promoter, and this consensus sequence is required for Notch-mediated SMA induction. This is the first evidence of the requirement for Notch activation in the regulation of SMA expression.

Key Words: endothelial cells • Notch • CSL • smooth muscle cells • smooth muscle actin • endothelial-to-mesenchymal transformation

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Either loss or gain of function of the Notch pathway causes defects in cardiovascular development in human, mouse, and zebrafish.^1,2 Notch mediates intercellular signals that affect proliferation, survival, and differentiation of endothelial and vascular smooth muscle cells (SMC).^3–7 We and others have recently shown that Jagged1–Notch interactions may participate in endocardial cushion formation by inducing endothelial-to-mesenchymal transformation (EMT).^3,8

Engagement of Notch receptors by their ligands results in a 2-step cleavage that releases the intracellular domain (NotchIC), permitting translocation to the nucleus. Presenilin-dependent -secretase activity is essential for the ultimate intramembrane clip that releases NotchIC.⁹ Following nuclear localization, NotchIC interacts with the DNA-binding factor CSL (also known as RBP-J and CBF1), resulting in transactivation of various promoters, such as those of the HES and HEY families.^10,11

Notch-mediated mesenchymal transformation results in loss of endothelial markers and induction of mesenchymal proteins such as smooth muscle -actin (SMA).³ However, the mechanism of Notch-induced SMA expression has not been studied. SMA is the most abundant protein in SMC and appears to play an important role in mechanotransduction and generation of traction forces in SMC as well as myofibroblasts.¹² Here we demonstrate that Notch-mediated upregulation of SMA is directly dependent on the activation and binding of CSL to the SMA promoter. Importantly, not only is Notch/CSL-dependent induction of SMA involved in EMT, but it is also required for SMA expression in SMC.

	Materials and Methods

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Cell Culture
The human microvascular endothelial cell line HMEC-1 (HMEC), human aortic endothelial cells (HAEC), and human umbilical vein endothelial cells (HUVEC) were obtained as previously described.^3,5 Primary human foreskin fibroblasts (HFF) were provided by Dr C. Sherlock (St. Paul’s Hospital, Vancouver, BC). Human aortic SMC (HASMC) were purchased from Cascade Biologics. Culture conditions are described in the expanded Materials and Methods section available in the online data supplement at http://circres.ahajournals.org.

Plasmids, Gene Transfer, and RNA Interference
Cells were transduced as previously described.^3,5 For a description of plasmids and details on small interfering RNA (siRNA), see the online data supplement.

Immunoblotting and Immunofluorescence Staining
Immunoblotting, immunostaining, and image acquisition were performed as described previously.⁵ Antibodies are listed in the online data supplement.

Luciferase Assay
The SMA-promoter luciferase construct (gift of F. Dandre and G. K. Owens, University of Virginia Health Sciences Center, Charlottesville) has been previously described.^3,13 See the online data supplement for more details.

Chromatin Immunoprecipitation Assay
HMEC transduced with LNCX or vector expressing Flag-tagged CSL were fixed in 1% formaldehyde, lysed, and sonicated. One percent of total chromatin was used as positive control for PCR (online data supplement).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
We first confirmed that Notch1IC induces SMA expression in endothelial cells by immunoblotting (Figure 1A). Activated Notch1 also induced expression of SMA in primary human fibroblasts (Figure 1B). Given that SMA is a marker of differentiation for SMC and that these cells express endogenous Notch1, Notch2, and Notch3, as well as the ligand Jagged1, we tested whether activated Notch and Jagged1-induced Notch activation would induce upregulation of SMA in HASMC.^5,14 Immunoblotting demonstrated that both Notch1IC and Jagged1-mediated Notch activation induced expression of SMA in SMC (Figure 1C and 1D). To determine whether Notch regulates SMA expression in SMC through endogenous Notch ligand–receptor interactions, HASMC transduced with vector alone (HASMC-vector) or Jagged1 (HASMC-Jagged1) were treated with vehicle or a -secretase inhibitor (GSI).^5,8 Inhibition of Notch processing blocked expression of SMA in control cells as well as in Jagged1 cocultures, indicating that in SMC the endogenous Notch pathway participates in the maintenance of SMA expression and that Jagged1-mediated induction of SMA is dependent on Notch activation (Figure 1E). These results indicate that the Notch pathway is a major regulator of the expression of SMA not only during EMT but also in fibroblasts and importantly in SMC.

View larger version (40K): [in this window] [in a new window]   Figure 1. Activation of the Notch pathway induces expression of SMA. A through C, HUVEC, HFF, or HASMC were transduced with empty vector (vec) or vector encoding Notch1IC (N1IC), and SMA expression was analyzed by immunoblotting. D, HASMC-vector (vec) and HASMC-Jagged1 (Jag) were analyzed for expression of SMA by immunoblotting. E, HASMC-vector and HASMC-Jagged1 were treated with vehicle alone (-) or with GSI, and SMA expression levels were analyzed by immunoblotting. Tubulin was used as a loading control.

Notch activation also induced expression of SMA mRNA and activated the SMA promoter as seen in a promoter-luciferase assay in HMEC and 293T cells (supplemental Figure I and data not shown), suggesting that Notch induces SMA through transcriptional activation.^3,13 The human SMA promoter contains a CSL consensus binding site (TGGGAA) beginning at –64 from the cap site that is conserved in apes and rodents (supplemental Figure II).^3,13 We thus tested whether CSL activation was sufficient to induce SMA expression. Transduction of constitutively active CSL (engineered by fusing CSL with the transcriptional activation domain of the herpes viral protein 16 [CSL-VP16]) was sufficient to induce expression of SMA in endothelial cells and fibroblasts (Figure 2A).¹⁵ In addition, transfection of CSL-VP16 was sufficient to activate the SMA promoter in endothelial cells, as demonstrated by promoter-luciferase assay (Figure 2B).

View larger version (58K): [in this window] [in a new window]   Figure 2. CSL activation is sufficient and necessary to induce SMA expression. A, HAEC and HFF were transduced with empty vector or vector encoding CSL-VP16. SMA expression was analyzed by immunofluorescence. Cell nuclei were counterstained with DAPI. B, HMEC were cotransfected with vector or CSL-VP16, SMA-WT, and constitutively active Renilla luciferase reporter. The graphs show relative luciferase activity (mean±SEM of 4 experiments, each done in triplicate). *P<0.01 compared with vector. C, HFF were transduced with Notch1IC (N1IC) or the empty vector (vec) and CSL-DN or its empty vector (vector) and analyzed by immunoblotting for expression of SMA. Tubulin was used as a loading control. D, HFF-vector (vec) and HFF-Notch1IC (N1IC) were infected with 1 of the 2 lentiviruses expressing siRNA targeting 2 different sequences of CSL (siCSLa and siCSLb) or control random siRNA (siRandom). Knockdown of CSL was confirmed by RT-PCR. Expression of SMA and tubulin were tested by immunoblotting.

To determine whether CSL is necessary for Notch-mediated SMA induction, HFF were double-transduced with Notch1IC and CSL-DN (dominant-negative CSL) or the empty vectors. Notch-induced morphological changes were lost in cells coexpressing Notch1IC and CSL-DN (data not shown). Immunoblotting showed decreased expression of SMA in cells transduced with CSL-DN and Notch1IC compared with cells transduced with Notch1IC and the empty vector (Figure 2C). Secondly, we used lentiviral transduction of short-hairpin RNAs to generate siRNAs targeting CSL (siCSL). Cells were infected with empty vector or Notch1IC and 1 of 2 lentiviral constructs targeting 2 different sequences of CSL (siCSLa or siCSLb) or a nonsilencing control (siRandom). Knock-down of CSL was confirmed by RT-PCR (Figure 2D). Cells infected with siCSLa or siCSLb and Notch1IC showed reduced expression of SMA compared with control cells (Figure 2D). Thus, Notch-mediated induction of SMA is mediated through activation of CSL.

To test whether the putative CSL-binding site in the SMA promoter is required for its activation, the consensus sequence was disrupted by site-directed mutagenesis. Endothelial cells were cotransfected with NotchIC or control vector and either the wild-type (SMA-WT) or CSL-binding site–mutated (SMA-mut) SMA-promoter luciferase constructs. Results show complete inhibition of Notch-dependent luciferase activation when the CSL-binding site is mutated (Figure 3A). To confirm a role for endogenous Notch/CSL signaling in regulation of the SMA promoter in SMC, we transfected HASMC with SMA-WT or SMA-mut (Figure 3B). Luciferase assays demonstrate that mutation of the CSL-binding site significantly reduces activation of the SMA promoter in SMC, suggesting a critical role for endogenous CSL activity in inducing and maintaining expression of SMA. To confirm that CSL directly binds the SMA promoter, chromatin immunoprecipitation assay (ChIP) assays were performed in HMEC transduced with vector encoding Flag-tagged CSL or the empty vector. PCR of Flag immunoprecipitated DNA using primers flanking the CSL consensus site confirmed that CSL directly binds the SMA promoter (Figure 3C).

View larger version (25K): [in this window] [in a new window]   Figure 3. The CSL consensus binding site is required for SMA expression. A, HMEC were cotransfected with vector or NotchIC, firefly luciferase constructs with upstream wild-type (SMA-WT) or mutated SMA promoters (SMA-mut), and CMV-driven Renilla luciferase reporter. The graph shows relative luciferase activity (mean±SEM of 4 experiments, each done in triplicate). *P<0.05 compared with vector and **P<0.05 compared with SMA-WT NotchIC. B, SMC were transfected with vector, SMA-WT, or SMA-mut and Renilla luciferase reporter. Graphs show luciferase activity relative to vector (mean±SEM of 3 experiments, each done in triplicate). *P<0.05 compared with vector. C, ChIP assay in HMEC expressing Flag-tagged CSL (CSL) or vector control. PCR with primers flanking the CSL consensus sequence in the SMA promoter was performed following immunoprecipitation with the Flag antibody (ChIP DNA). One percent of total chromatin was used as a positive control for PCR (Input DNA).

In summary, this study shows that Notch/CSL signaling directly regulates expression of SMA by a transcriptional mechanism that requires binding of CSL to the SMA promoter. Of note, Notch/CSL-mediated induction of SMA is involved in EMT and fibroblast acquisition of SMA, as well as in the maintenance of SMA expression in SMC. These data also trigger more questions regarding the role of Notch in the vasculature. For instance, what are the factors that determine cell-type and context-specific effects of Notch in the endothelial and mural compartments? Notch1 and Jagged1 have been detected in both endothelial cells and SMC, and whether specific Notch or ligand expression (eg, Notch3 in SMC and Notch4 and Dll4 in endothelial cells) contributes to these decisions remains to be investigated. On a broader perspective, given that Notch appears to play a role in tissue regeneration and that myofibroblasts and SMC appear to use SMA to transmit mechanical forces through the cell, our data provide a potential explanation of the role of Notch in wound healing and vascular remodeling.^12,16,17

	Acknowledgments

 
We thank Denise McDougal for assistance with cell sorting and Dana Wong for technical help.

Sources of Funding

This research was supported by grants to A.K. from the Heart and Stroke Foundation of British Columbia and the Yukon and the Canadian Institutes of Health Research. M.N. was supported by a fellowship from the Canadian Institutes of Health Research and a Research Trainee Award from the Michael Smith Foundation for Health Research. Y.F. and K.N. are supported by Research Trainee Awards from the Michael Smith Foundation for Health Research. A.K. is a scholar of the Michael Smith Foundation for Health Research.

Disclosures

None.

	Footnotes

 
Original received March 23, 2006; revision received April 27, 2006; accepted May 18, 2006.

	References

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This Article Abstract Full Text (PDF) Data Supplement All Versions of this Article: 98/12/1468    most recent 01.RES.0000229683.81357.26v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Noseda, M. Articles by Karsan, A. Search for Related Content PubMed PubMed Citation Articles by Noseda, M. Articles by Karsan, A. Related Collections Angiogenesis Smooth muscle proliferation and differentiation Endothelium/vascular type/nitric oxide Other Vascular biology Other Research