Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro

Cancer patients treated for venous thromboembolism with low molecular weigh t heparin (LMWH) have a better survival rate than patients treated with unf ractionated heparin (UFH). Because fibrin-associated angiogenesis is an imp ortant determinant in the progression and metastasis of many solid tumors, the effects of heparins on in vitro angiogenesis were investigated. Both UF H and LMWH inhibited bFGF-induced proliferation of human microvascular endo thelial cells (hMVECs) to the same the extent (36-60%). VEGF(165)-induced p roliferation was inhibited to a to a lesser extent (19-33%). Turbidity meas urements and electron microscopy showed that the presence of LMWH during po lymerization of the fibrin matrix led to a more transparent rigid network w ith thin fibrin bundles, whereas the presence of UFA resulted in a more opa que 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 mat rix, and stimulated the cells with basic fibroblast growth factor plus tumo r necrosis factor Lu to induce capillary-like tubular structures, The forma tion of capillary-like tubular structures was retarded with matrices polyme rized in the presence of LMWH (46% inhibition compared with a control matri x for both 1.5 and 10 units/ml LMWH), whereas matrices polymerized in the p resence of UFH facilitated tubular structure formation (72 and 36% stimulat ion compared with a control matrix for 1.5 and 10 units/ml UFH, respectivel y). Similar results were obtained for cells stimulated with vascular endoth elial growth factor plus tumor necrosis factor alpha. These data demonstrat e the inhibitory effect of heparins on proliferation of hMTECs and provide a novel mechanism by which LMWH may affect tumor progression, namely reduce d ingrowth of microvascular structures in a fibrinous stroma matrix by rend ering it less permissive for invasion.