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Unfractionated and Low Molecular Weight Heparin Affect Fibrin Structure and Angiogenesis in Vitro¹

Gaubius Laboratory TNO-PG, 2333 CK Leiden, the Netherlands [A. C., E. P., P. K., V. W. M. v. H.]; Departments of Cell Biology and Histology [S. M. S., C. V. N.] and Vascular Medicine [S. M. S.], Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Vascular Biology, Thrombosis Research Institute, SW3 6LR London, United Kingdom [F. L.]; Department of Physiology, Institute for Cardiovascular Research, Vrije Universiteit, 1081 BT Amsterdam, the Netherlands [V. W. M. v. H.]

Cancer patients treated for venous thromboembolism with low molecular weight heparin (LMWH) have a better survival rate than patients treated with unfractionated heparin (UFH). Because fibrin-associated angiogenesis is an important determinant in the progression and metastasis of many solid tumors, the effects of heparins on in vitro angiogenesis were investigated. Both UFH and LMWH inhibited bFGF-induced proliferation of human microvascular endothelial cells (hMVECs) to the same the extent (36–60%). VEGF₁₆₅-induced proliferation was inhibited to a to a lesser extent (19–33%). Turbidity measurements and electron microscopy showed that the presence of LMWH during polymerization of the fibrin matrix led to a more transparent rigid network with thin fibrin bundles, whereas the presence of UFH resulted in a more opaque more porous network with thick fibrin fibers. We used a human in vitro angiogenesis model, which consisted of hMVECs seeded on top of a fibrin matrix, and stimulated the cells with basic fibroblast growth factor plus tumor necrosis factor to induce capillary-like tubular structures. The formation of capillary-like tubular structures was retarded with matrices polymerized in the presence of LMWH (46% inhibition compared with a control matrix for both 1.5 and 10 units/ml LMWH), whereas matrices polymerized in the presence of UFH facilitated tubular structure formation (72 and 36% stimulation compared with a control matrix for 1.5 and 10 units/ml UFH, respectively). Similar results were obtained for cells stimulated with vascular endothelial growth factor plus tumor necrosis factor . These data demonstrate the inhibitory effect of heparins on proliferation of hMVECs and provide a novel mechanism by which LMWH may affect tumor progression, namely reduced ingrowth of microvascular structures in a fibrinous stroma matrix by rendering it less permissive for invasion.

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