Authors |
Surovi Hazarika, MD, PhD; Ayotunde O Dokun, MD, PhD; Younjun Li, MD; Aleksander S. Popel MS, PhD; Christopher D. Kontos, MD; Brian H. Annex, MD
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Submitted By |
Thomas Coffman on 2/2/2007 |
Status |
Published |
Journal |
Circulation research |
Year |
2007 |
Date Published |
10/26/2007 |
Volume : Pages |
101(9) : 948 - 956 |
PubMed Reference |
17823371 |
Abstract |
Objective: Deficient angiogenesis following ischemia may contribute to worse outcomes of peripheral arterial disease (PAD) in patients with diabetes mellitus. Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis in PAD. We tested the hypothesis that in diabetes excess production of soluble Flt-1 could account for impaired angiogenesis. Methods: Hindlimb skeletal muscle from diet-induced, type II, diabetic (DM) and age-matched normal chow fed (NC) mice was collected, at baseline and 3 days after hindlimb ischemia, and analyzed for expression of VEGF (n = 10/group), full length and soluble VEGF receptors and downstream VEGF signaling (n = 20/group), using ELISA, RT-PCR and western blots (WB). Results: At baseline, DM mice had increased VEGF (NC vs. DM, 26.6?2.6 vs. 53.5?8.8 pg/mg protein, p<0.05); decreased soluble and membrane bound VEGFR-1 (NC vs. DM; sVEGFR1; 1.44?0.30 vs. 0.85?0.08; VEGFR1 1.03?0.10 vs. 0.72?0.10; WB-densitometry, p<0.05); decreased VEGF signaling (NC vs. DM; p-AKT/AKT 0.76?0.2 vs. 0.38?0.1; p-eNOS/eNOS 0.36?0.06 vs. 0.25?0.04, WB-densitometry; p< 0.05); and no change in VEGF R2. Following ischemia, both DM and NC had comparable increase in VEGF A. Although sVEGFR1 and VEGFR1 expression increased in both groups, the fold-increase from baseline was greater in DM. Conclusions: In DM, there are higher levels of VEGF, lower VEGFR1 and sVEGFR1 with lower receptor/signaling. Following ischemia, VEGF A increases in both NC and DM but sVEGFR1 and VEGFR1 increases disproportionately in DM, which may limit VEGF ligand binding to VEGFR2 and extent of the adaptive angiogenic response.
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