Hyperhomocysteinemia inhibits post-injury reendothelialization in mice

doi:10.1016/j.cardiores.2005.08.016

Cardiovascular Research 2006 69(1):253-262; doi:10.1016/j.cardiores.2005.08.016

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Hyperhomocysteinemia inhibits post-injury reendothelialization in mice

Hongmei Tan^a^,c^,d, Xiaohua Jiang^a^,c, Fan Yang^a^,c, Zhaohui Li^a^,c, Dan Liao^a^,c, JoAnn Trial^a, Mark J. Magera^e, William Durante^a^,b^,c, Xiaofeng Yang^a and Hong Wang^a^,c^,*

^aDepartment of Medicine, Baylor College of Medicine, United States
^bDepartment of Pharmacology, Baylor College of Medicine, United States
^cVA Medical Center, Houston, Texas 77030, United States
^dSun Yat-sen University School of Medicine, Guangzhou, China
^eMayo Clinic, Rochester, Minnesota 55905, United States

^* Corresponding author. Houston VA Medical Center, Baylor College of Medicine, 2002 Holcombe Blvd. Houston, TX, 77030, United States. Tel.: +1 713 794 7568; fax: +1 713 794 7165. Email address: hongw{at}bcm.tmc.edu

Objective: Hyperhomocysteinemia (HHcy) is a risk factor forcardiovascular disease and has been reported to inhibit endothelialcell (EC) growth. Notwithstanding, precisely how HHcy regulatesEC growth in vivo remains unknown. In this study, we establisheda mouse model of endothelial injury and reendothelializationand examined the role and mechanism of HHcy in endothelial repair.

Methods and results: A mouse model of carotid artery air-dryendothelium denudation and reendothelialization was establishedand used to evaluate post-injury endothelial repair in micewith the gene deletion of cystathionine-β-synthase (CBS).Moderate and severe HHcy were induced in CBS^+/+ and CBS^–/+mice through a high-methionine diet. Post-injury reendothelialization,which correlated with increased post-injury neointima formation,was impaired in severe HHcy mice. To elucidate the underlyingmechanism, we examined circulating endothelial progenitor cells(EPC) in HHcy mice and studied the effect of homocysteine (Hcy)on proliferation, migration, and adhesion of human umbilicalvein endothelial cells (HUVEC). The peripheral EPC populationwas not significantly altered in HHcy mice. Hcy had a profoundinhibitory effect on EC proliferation and migration at physiologicallyrelevant concentrations and inhibited EC adhesion at concentrationsof 200 µM and higher.

Conclusion: We have established a convenient and accurate mousemodel of carotid injury in which the reendothelialization processcan be precisely quantified. In addition, we have observed impairedreendothelialization and increased neointimal formation in severeHHcy mice. The capacity of Hcy to inhibit proliferation andmigration of EC may be responsible for impaired reendothelializationand contribute to arteriosclerosis in HHcy.

KEYWORDS Homocysteine; Carotid injury; Reendothelialization

Time for primary review 28 days

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