Impaired Angiogenesis Following Hind-Limb Ischemia in Type 2 Diabetes Mellitus:
Differential Regulation of VEGFR1, R2, and Soluble VEGFR-1
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
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


Flt1FMS-like tyrosine kinase 1
Rykreceptor-like tyrosine kinase
Vegfavascular endothelial growth factor A