Abstract
BackgroundHuman studies of therapeutic angiogenesis, stem-cell, and progenitor-cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied.Methodology/Principal FindingsWe measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients undergoing elective percutaneous coronary intervention. Compared to baseline values, sFLT1 and PlGF levels increased by 2629±313% and 253±54%, respectively, within 30 minutes of UFH therapy (p<0.01 for both; n = 8). VEGF levels decreased by 93.2±5% in patients treated with UFH (p<0.01 versus baseline). No change in sEng levels were observed after UFH therapy. No changes in sFLT1, PlGF, VEGF, or sEng levels were observed in any patients receiving bivalirudin (n = 8). To further explore the direct effect of anticoagulation on circulating angiogenic peptides, adult, male wild-type mice received venous injections of clinically dosed UFH or bivalirudin. Compared to saline controls, sFLT1 and PlGF levels increased by >500% (p<0.01, for both) and VEGF levels increased by 221±101% (p<0.05) 30 minutes after UFH treatment. Bivalirudin had no effect on peptide levels. To study the cellular origin of peptides after anticoagulant therapy, human coronary endothelial cells were treated with UFH and demonstrated increased sFLT1 and PlGF levels (ANOVA p<0.01 for both) with reduced VEGF levels (ANOVA p<0.05). Bivalirudin had no effect on peptide levels in vitro.Conclusions/SignificanceCirculating levels of sFLT1, PlGF, and VEGF are significantly altered by UFH, while bivalirudin therapy has no effect. These findings may have significant implications for clinical studies of therapeutic angiogenesis, stem-cell and progenitor-cell therapy.
Highlights
Since the discovery of vascular endothelial growth factor (VEGF), therapeutic angiogenesis, stem-cell and progenitor-cell therapy have attracted interest as an innovative approaches to manage end-stage ischemic coronary and peripheral artery disease [1], [2]
The primary finding of our study is that administration of unfractionated heparin (UFH) results in significant changes in circulating levels of angiogenic peptides, while bivalirudin does not. soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) were increased, while VEGF165 levels were decreased with UFH
We demonstrated these differences in vivo using human subjects undergoing percutaneous coronary intervention (PCI) for coronary artery disease and healthy C57/ Bl6 mice, and in vitro using Human coronary artery endothelial cells (HCAEC)
Summary
Since the discovery of vascular endothelial growth factor (VEGF), therapeutic angiogenesis, stem-cell and progenitor-cell therapy have attracted interest as an innovative approaches to manage end-stage ischemic coronary and peripheral artery disease [1], [2]. Heparin (unfractionated or low-molecular weight) is commonly used for the treatment of coronary and peripheral artery disease, especially in the settings of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI). Recent data have shown that heparin administration (in either unfractionated or low-molecular weight form) increases levels of soluble fms-like tyrosine kinase-1 (sFlt1) [3,4,5,6], a circulating splice variant of the VEGF receptor 1 that is expressed by endothelial cells, vascular smooth muscle cells, and monocytes [7,8]. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied
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