We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia.
- Authors
Bosch-Marcé, Marta; Pola, Roberto; Wecker, Andrea B; Silver, Marcy; Weber, Alberto; Luedemann, Corinne; Curry, Cynthia; Murayama, Toshinori; Kearny, Marianne; Young-sup Yoon; Malinow, M. René; Asahara, Takayuki; Isner, Jeffrey M.; Losordo, Douglas W.
- Abstract
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 β-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.
- Subjects
VASCULAR diseases; DIABETES; HYPERCHOLESTEREMIA; VASCULAR endothelial growth factors; ISCHEMIA; ANIMAL models in research
- Publication
Vascular Medicine, 2005, Vol 10, Issue 1, p15
- ISSN
1358-863X
- Publication type
Article
- DOI
10.1191/1358863x05vm585oa