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CLINICAL RESEARCH: PERIPHERAL VASCULAR DISEASE

Plasma Levels of Soluble Tie2 and Vascular Endothelial Growth Factor Distinguish Critical Limb Ischemia From Intermittent Claudication in Patients With Peripheral Arterial Disease

Clarence M. Findley, PhD^_*,,, Robert G. Mitchell, MD^_*, Brian D. Duscha, MS^_*, Brian H. Annex, MD^_*, and Christopher D. Kontos, MD, FACC^_*,,_*

^_* Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina
School of Medicine, Duke University Medical Center, Durham, North Carolina
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
Division of Cardiology, Department of Medicine, Durham Veterans Affairs Medical Center, Durham, North Carolina.

Manuscript received August 20, 2007; revised manuscript received December 28, 2007, accepted February 7, 2008.

^_* Reprint requests and correspondence: Dr. Christopher D. Kontos, Box 3629 DUMC, Duke University Medical Center, Durham, North Carolina 27710. (Email: cdkontos{at}duke.edu).

Presented in part at the 17th Annual Scientific Sessions of the Society for Vascular Medicine and Biology, Philadelphia, Pennsylvania, June 2–3, 2006.

Objectives: Our purpose was to determine whether factors that regulate angiogenesis are altered in peripheral arterial disease (PAD) and whether these factors are associated with the severity of PAD.

Background: Alterations in angiogenic growth factors occur in cardiovascular disease (CVD), but whether these factors are altered in PAD or correlate with disease severity is unknown.

Methods: Plasma was collected from patients with PAD (n = 46) and healthy control subjects (n = 23). Peripheral arterial disease patients included those with intermittent claudication (IC) (n = 23) and critical limb ischemia (CLI) (n = 23). Plasma angiopoietin-2 (Ang2), soluble Tie2 (sTie2), vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR-1), and placenta growth factor (PlGF) were measured by enzyme-linked immunoadsorbent assay. In vitro, endothelial cells (ECs) were treated with recombinant VEGF to investigate effects on sTie2 production.

Results: Plasma concentrations of sTie2 (p < 0.01), Ang2 (p < 0.001), and VEGF (p < 0.01), but not PlGF or sVEGFR-1, were significantly greater in PAD patients compared with control subjects. Plasma Ang2 was significantly increased in both IC and CLI compared with control subjects (p < 0.0001), but there was no difference between IC and CLI. Plasma VEGF and sTie2 were similar in control subjects and IC but were significantly increased in CLI (p < 0.001 vs. control or IC). Increased sTie2 and VEGF were independent of CVD risk factors or the ankle-brachial index, and VEGF treatment of ECs in vitro significantly increased sTie2 shedding.

Conclusions: Levels of VEGF and sTie2 are significantly increased in CLI, and sTie2 production is induced by VEGF. These proteins may provide novel biomarkers for CLI, and sTie2 may be both a marker and a cause of CLI.

Key Words: peripheral arterial disease • soluble Tie2 • vascular endothelial growth factor • critical limb ischemia • biomarkers

Abbreviations and Acronyms   ABI = ankle-brachial index   Ang2 = angiopoietin-2   CLI = critical limb ischemia   CVD = cardiovascular disease   HUVEC = human umbilical vein endothelial cell   IC = intermittent claudication   PAD = peripheral arterial disease   PlGF = placenta growth factor   sTie2 = soluble Tie2   sVEGFR-1 = soluble vascular endothelial growth factor receptor 1   VEGF = vascular endothelial growth factor

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