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Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Roberto Pola

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Andrea B Wecker

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Marcy Silver

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Alberto Weber

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Corinne Luedemann

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Cynthia Curry

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Toshinori Murayama

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Marianne Kearney

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Young-sup Yoon

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

M René Malinow

Oregon Regional Primate Research Center, Division of Cardiology, Oregon Health Sciences University, Beaverton, OR, USA

Takayuki Asahara

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

Jeffrey M Isner

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA, Deceased

Douglas W Losordo

Department of Medicine (Cardiovascular Research), Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA, douglas.losordo{at}tufts.edu

Hyperhomocyst(e)inemia (HH) is an established independent risk factor for coronary, cerebral and peripheral vascular diseases. Recent studies have indicated that certain cardiovascular risk factors, including diabetes and hypercholesterolemia, impair expression of vascular endothelial growth factor (VEGF) and endogenous angiogenesis. In this study, we investigate the impact of moderate HH on angiogenesis and VEGF pathway in a mouse model of hindlimb ischemia. Upon induction of unilateral hindlimb ischemia, endogenous angiogenesis, expression of VEGF, and phosphorylation of the VEGF receptor Flk-1 were evaluated in mice heterozygous for a deletion of the cystathionine -synthase gene (CBS) and compared with those observed in CBS/mice. CBS/mice exhibit moderate HH, as demonstrated by measuring plasma total homocyst(e)ine (tHcy) levels, which were significantly higher in these animals compared with CBS/mice (4.77 0.82 vs 2.10 0.28, p 0.01). Twenty-eight days after induction of ischemia, hindlimb blood flow was significantly reduced in CBS/mice compared with CBS/animals (0.49 0.03, n 12 vs 0.71 0.09, n 10; p 0.05). In addition, there was a significant negative correlation between plasma homocyst(e)ine levels and the laser Doppler perfusion ratio in CBS/mice (p 0.0087, r 0.7171). While VEGF expression and Flk-1 phosphorylation were not impaired in the ischemic muscles of CBS/mice, phosphorylation of the endothelial cell survival factor Akt was significantly inhibited by homocyst(e)ine in a dose-dependent manner in human umbilical vein endothelial cell (HUVECs) in vitro. In conclusion, our findings demonstrate that endogenous angiogenesis is inversely related to plasma levels of homocyst(e)ine in genetically engineered, heterozygous mice with moderate HH. This impairment, however, is not dependent on reduced expression of VEGF or impaired phosphorylation of its receptor Flk-1. In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH.

Key Words: Akt • angiogenesis • Flk-1 • hyperhomocyst(e)inemia • ischemia • VEGF

Vascular Medicine, Vol. 10, No. 1, 15-22 (2005)
DOI: 10.1191/1358863x05vm585oa


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