Published online before print September 6, 2007, doi: 10.1161/CIRCRESAHA.107.160630
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Submitted on February 19, 2007
Revised on July 25, 2007
Accepted on August 27, 2007
Impaired Angiogenesis Following Hindlimb Ischemia in Type 2 Diabetes Mellitus. Differential Regulation of Vascular Endothelial Growth Factor Receptor 1 and Soluble VEGFR-1
Surovi Hazarika ;
From the Division of Cardiology (S.H., A.O.D., Y.L., C.D.K., B.H.A.), Department of Medicine, Durham Veterans Affairs and Duke University Medical Center, NC; and Department of Biomedical Engineering (A.S.P.), Johns Hopkins University School of Medicine, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: annex001{at}mc.duke.edu.
Deficient angiogenesis following ischemia may contribute to worse outcomes of peripheral arterial disease in patients with diabetes mellitus (DM). Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis. We hypothesized that in peripheral arterial disease, maladaptive changes in VEGF ligand/receptor expression could account for impaired angiogenesis in DM. Skeletal muscle from diet-induced, type 2 diabetic (DM) and age-matched normal chow (NC)-fed mice was collected at baseline and 3 and 10 days after hindlimb ischemia and analyzed for expression of VEGF (n=10 per group), full-length VEGF receptor (VEGFR)-1, soluble VEGFR-1, and markers of downstream VEGF signaling (n=20 per group) using ELISA, RT-PCR, and Western blots. In the absence of ischemia, DM mice had increased VEGF (NC versus DM: 26.6±2.6 versus 53.5±8.8 pg/mg protein; P<0.05), decreased soluble and membrane-bound VEGFR-1 (NC versus DM: 1.44±0.30 versus 0.85±0.08 and 1.03±0.10 versus 0.72±0.10, respectively; P<0.05). decreased phospho-AKT/AKT and phospho–endothelial NO synthase/endothelial NO synthase (NC versus DM: 0.76±0.2 versus 0.38±0.1 and 0.36±0.06 versus 0.25±0.04, respectively; P<0.05), and no change in VEGFR-2. Following ischemia, both DM and NC had comparable increases in VEGF-A. VEGFR-1 and soluble VEGFR-1 expression increased in both groups, but the fold increase was significantly greater in DM. These data demonstrate that soluble VEGFR-1, an angiogenesis inhibitor, is regulated in skeletal muscle by type 2 DM and ischemia. In the absence of ischemia, despite reductions in both soluble VEGFR-1 and VEGFR-1, VEGF ligand signaling is lower in DM compared with controls. Following ischemia, maladaptive upregulation of these receptors further reduces the capacity of VEGF to induce an angiogenic response, which may provide a novel target for therapy.
Key words: vascular disease • growth factors • nitric oxide
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