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Endothelial NO synthase deficiency promotes smooth muscle progenitor cells in association with upregulation of stromal cell-derived factor-1alpha in a mouse model of carotid artery ligation.
Arterioscler Thromb Vasc Biol. 2006 Apr; 26(4):765-72.AT

Abstract

BACKGROUND

Endothelial NO deficiency (endothelial NO synthase [eNOS]-knockout [KO]) enhanced smooth muscle cell (SMC)-rich neointimal lesion formation in a mouse model of carotid artery ligation (CAL). Recent evidence indicated that stromal cell-derived factor-1alpha (SDF-1alpha)-mediated recruitment of circulating SMC progenitor cells substantially contributed to the SMC-rich neointimal hyperplasia induced by vascular injury. The goal of this study was to investigate the effects of eNOS deficiency on the expression of SDF-1alpha and mobilization of circulating SMC progenitor cells in CAL model.

METHODS AND RESULTS

Two- to 3-month-old C57BL/6J wild-type (WT) and eNOS-KO mice were evaluated 1, 2, or 4 weeks after CAL. CAL-induced expression of SDF-1alpha, as detected by immunohistochemical staining and further quantified by ELISA in the ligated carotid arteries, was moderate and transient with a peak at 1 week in WT mice. SDF-1alpha expression was significantly higher at 1 week and persisted through 2 weeks in eNOS-KO mice. CAL was associated with increased circulating stem cell antigen-1(+) (Sca-1(+))/c-Kit(-)/Lin- cells (interpreted as SMC progenitor cells), which peaked at 1 week in WT mice. This effect was also significantly greater and longer-lasting in eNOS-KO than WT mice. The number of circulating Sca-1(+)/c-Kit(-)/Lin- cells was positively correlated with the expression of SDF-1alpha but not vascular endothelial growth factor in the ligated carotid arteries. Furthermore, immunostaining showed abundant Sca-1-positive cells in the adventitia of the 1-week ligated carotid arteries from eNOS-KO mice but not in WT mice. We also determined that eNOS deficiency enhanced CAL-induced intimal cell proliferation in the ligated arteries as detected by proliferating cell nuclear antigen staining but did not induce cell apoptosis as detected by staining for active caspase-3.

CONCLUSIONS

Our results indicate that eNOS deficiency exacerbates CAL-induced expression of SDF-1alpha and its receptor CXCR4. This is correlated with an increase in Sca-1(+) cells in peripheral blood and adventitia, which may contribute to vascular remodeling and SMC-rich neointimal lesion formation. This suggests that constitutive eNOS inhibits SDF-1alpha expression and provides an important vasculoprotective mechanism for intact endothelium to limit SMC proliferation and recruitment in response to vascular injury.

Authors+Show Affiliations

Department of Internal Medicine, School of Medicine, University of California, Davis, CA 95616, USA. lnzhang@ucdavis.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16456092

Citation

Zhang, Le-Ning, et al. "Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-derived Factor-1alpha in a Mouse Model of Carotid Artery Ligation." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 4, 2006, pp. 765-72.
Zhang LN, Wilson DW, da Cunha V, et al. Endothelial NO synthase deficiency promotes smooth muscle progenitor cells in association with upregulation of stromal cell-derived factor-1alpha in a mouse model of carotid artery ligation. Arterioscler Thromb Vasc Biol. 2006;26(4):765-72.
Zhang, L. N., Wilson, D. W., da Cunha, V., Sullivan, M. E., Vergona, R., Rutledge, J. C., & Wang, Y. X. (2006). Endothelial NO synthase deficiency promotes smooth muscle progenitor cells in association with upregulation of stromal cell-derived factor-1alpha in a mouse model of carotid artery ligation. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(4), 765-72.
Zhang LN, et al. Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-derived Factor-1alpha in a Mouse Model of Carotid Artery Ligation. Arterioscler Thromb Vasc Biol. 2006;26(4):765-72. PubMed PMID: 16456092.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelial NO synthase deficiency promotes smooth muscle progenitor cells in association with upregulation of stromal cell-derived factor-1alpha in a mouse model of carotid artery ligation. AU - Zhang,Le-Ning, AU - Wilson,Dennis W, AU - da Cunha,Valdeci, AU - Sullivan,Mark E, AU - Vergona,Ronald, AU - Rutledge,John C, AU - Wang,Yi-Xin, Y1 - 2006/02/02/ PY - 2006/2/4/pubmed PY - 2006/7/15/medline PY - 2006/2/4/entrez SP - 765 EP - 72 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 26 IS - 4 N2 - BACKGROUND: Endothelial NO deficiency (endothelial NO synthase [eNOS]-knockout [KO]) enhanced smooth muscle cell (SMC)-rich neointimal lesion formation in a mouse model of carotid artery ligation (CAL). Recent evidence indicated that stromal cell-derived factor-1alpha (SDF-1alpha)-mediated recruitment of circulating SMC progenitor cells substantially contributed to the SMC-rich neointimal hyperplasia induced by vascular injury. The goal of this study was to investigate the effects of eNOS deficiency on the expression of SDF-1alpha and mobilization of circulating SMC progenitor cells in CAL model. METHODS AND RESULTS: Two- to 3-month-old C57BL/6J wild-type (WT) and eNOS-KO mice were evaluated 1, 2, or 4 weeks after CAL. CAL-induced expression of SDF-1alpha, as detected by immunohistochemical staining and further quantified by ELISA in the ligated carotid arteries, was moderate and transient with a peak at 1 week in WT mice. SDF-1alpha expression was significantly higher at 1 week and persisted through 2 weeks in eNOS-KO mice. CAL was associated with increased circulating stem cell antigen-1(+) (Sca-1(+))/c-Kit(-)/Lin- cells (interpreted as SMC progenitor cells), which peaked at 1 week in WT mice. This effect was also significantly greater and longer-lasting in eNOS-KO than WT mice. The number of circulating Sca-1(+)/c-Kit(-)/Lin- cells was positively correlated with the expression of SDF-1alpha but not vascular endothelial growth factor in the ligated carotid arteries. Furthermore, immunostaining showed abundant Sca-1-positive cells in the adventitia of the 1-week ligated carotid arteries from eNOS-KO mice but not in WT mice. We also determined that eNOS deficiency enhanced CAL-induced intimal cell proliferation in the ligated arteries as detected by proliferating cell nuclear antigen staining but did not induce cell apoptosis as detected by staining for active caspase-3. CONCLUSIONS: Our results indicate that eNOS deficiency exacerbates CAL-induced expression of SDF-1alpha and its receptor CXCR4. This is correlated with an increase in Sca-1(+) cells in peripheral blood and adventitia, which may contribute to vascular remodeling and SMC-rich neointimal lesion formation. This suggests that constitutive eNOS inhibits SDF-1alpha expression and provides an important vasculoprotective mechanism for intact endothelium to limit SMC proliferation and recruitment in response to vascular injury. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/16456092/Endothelial_NO_synthase_deficiency_promotes_smooth_muscle_progenitor_cells_in_association_with_upregulation_of_stromal_cell_derived_factor_1alpha_in_a_mouse_model_of_carotid_artery_ligation_ L2 - https://www.ahajournals.org/doi/10.1161/01.ATV.0000207319.28254.8c?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -