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Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia
- Source :
- Vascular Medicine. 10:15-22
- Publication Year :
- 2005
- Publisher :
- SAGE Publications, 2005.
-
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 angiogen- esis 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, phos- phorylation 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 recep- tor Flk-1. In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH.
- Subjects :
- Vascular Endothelial Growth Factor A
medicine.medical_specialty
Angiogenesis
Hyperhomocysteinemia
Ischemia
Neovascularization, Physiologic
Mice, Inbred Strains
Hindlimb
030204 cardiovascular system & hematology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Animals
Medicine
030212 general & internal medicine
Phosphorylation
Protein kinase B
biology
business.industry
medicine.disease
Vascular Endothelial Growth Factor Receptor-2
Cystathionine beta synthase
Endothelial stem cell
Vascular endothelial growth factor
Disease Models, Animal
Endocrinology
chemistry
biology.protein
Human umbilical vein endothelial cell
Cardiology and Cardiovascular Medicine
business
Subjects
Details
- ISSN :
- 14770377 and 1358863X
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Vascular Medicine
- Accession number :
- edsair.doi.dedup.....cf78b41828bbd0b276a16e7e2b4c4cf0