Increase in GLUT1 in smooth muscle alters vascular contractility and increases inflammation in response to vascular injury.
OBJECTIVE
The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease.


RESULTS
A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3, P<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10, P<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4, P<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4, P<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4, P<0.003).


CONCLUSIONS
In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-β activity.
University of Minnesota, Minneapolis, MN 55455, USA.
Neeta
N
Adhikari
David L
DL
Basi
Marjorie
M
Carlson
Ami
A
Mariash
Zhigang
Z
Hong
Ute
U
Lehman
Sureni
S
Mullegama
Edward K
EK
Weir
Jennifer L
JL
Hall
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000097:blood; D006242:Haptoglobins / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D020556:Neutrophil Infiltration; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D015854:Up-Regulation; D014661:Vasoconstriction
D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005230:Fatty Acids, Nonesterified; D051272:Glucose Transporter Type 1; D006242:Haptoglobins; D007328:Insulin; D008840:Microfilament Proteins; D009124:Muscle Proteins; C495677:SLC2A1 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C051615:transgelin; D003847:Deoxyglucose; D005978:Glutathione