Reversal of angiogenic growth factor upregulation by revascularization of lower limb ischemia.

Abstract

Tissue kallikrein (tK) and vascular endothelial growth factor (VEGF) are potent angiogenic agents. Upregulation of tK or VEGF was documented in animal models of acute ischemia, yet it remains unknown whether these endothelial cell mitogens are overexpressed in chronic peripheral vascular insufficiency. Circulating tK and VEGF were measured in 36 patients with symptomatic peripheral vascular disease before and after surgical revascularization. In 6 patients without symptoms at rest, tK was assayed after exercise stress test. VEGF levels fell within the normal range in all patients (96+/-11 versus 109+/-13 pg/mL in healthy control subjects, P=NS) and remained unchanged after revascularization. In contrast, tK expression was upregulated in 34 of 36 patients (1107+/-203 versus 85+/-10 pg/mL in control subjects, P<0.05), with no further increase after exercise. Tissue kallikrein levels in the venous effluent of ischemic limbs were found to be positively correlated with the number of angiographically recognizable collateral vessels (P<0.001). Follow-up studies documented reversal of tK upregulation after revascularization (P<0.01), whereas no change was observed in venous samples from untouched legs. Induction of tK could represent a compensatory response to chronic arterial insufficiency, attempting to maintain an adequate tissue perfusion. Heterogeneous statement of growth factors may have important implications in reparative and therapeutic angiogenesis.