The influence of unfractionated and low-molecular weight heparins on the properties of human umbilical vein endothelial cells (HUVEC).

Abstract

Heparins, as anticoagulants widely used in the prophylaxis and treatment of many conditions connected with hypercoagulability, have a potent effect on the vascular endothelium. Unfractionated Heparin (UFH) is characterized by relatively low biological accessibility, short activity time, binding of numerous proteins, as well as unfavorable influence on endothelium and blood platelets. Low-Molecular Weight Heparins (LMWHs), formed by chemical and enzymatic UFH depolymerizations, show a significantly more favorable impact on endothelium, which was confirmed on the HUVEC cultures study models. The studies on the heparins' modulation of angiogenesis process proved the superiority of LMWHs over UFH. It was connected with a better deactivation of growth factors' receptors (e.g. for VEGF165, FGF-2). Comparing the effects of LMWHs and UFH on haemostatic and antiangiogenic properties of HUVEC, significant differences were found as well. A new effect, engaging these compounds in the pathomechanism of an excessive osteoclastogenesis via osteoprotegerin /RANKL/RANK pathway has been discovered recently.

Heparin-Like Drugs with Antiangiogenic Activity

“…LMWH present important advantages if compared to UFH: enhanced bioavailability after subcutaneous administration, prolonged half-life and more interesting pharmacokinetic properties, reduced thrombocytopenia and a more predictable dose response (Grande & Caparro, 2005;Khorana et al, 2003). (Amirkhosravi et al, 2003;Gasowska et al, 2009;Mousa & Mohamed, 2004a;Mousa & Mohamed, 2004b;Mousa & Petersen, 2009;Norrby, 2006) Dalteparin Fragmin Nitrous acid depolymerization 6.000 (Khorana et al, 2003;Marchetti et al, 2008;Norrby, 2006;Norrby & Nordenhem, 2010;Takahashi et al, 2005) Enoxaparin Clexane…”

“…Benzylation and alkaline hydrolysis 4.500 (Khorana et al, 2003;Marchetti et al, 2008;Norrby, 2000;Norrby, 2006) Nadroparin Fraxiparin Nitrous acid depolymerization 4.500 (Debergh et al, 2010;Khorana et al, 2003;Norrby, 2000) Reviparin Clivarine Nitrous acid depolymerization 4.500 (Collen et al, 2000;Gasowska et al, 2009;Mousa & Petersen, 2009;Norrby, 2006) Second generation heparin…”

“…Moreover, tissue factor (TF) and its natural inhibitor (TFPI) are also important heparin-binding proteins that perform well-recognized roles in the regulation of angiogenesis, tumor growth and metastasis (Bobek & Kobarik, 2004;Borsig, 2010;Debergh et al, 2010;Norrby, 2006). LMWH may influence angiogenesis through modulation of the expression of angiogenic growth factors (VEGF and bFGF) and their inhibitors (Dogan et al, 2011;Gasowska et al, 2009;Mousa & Petersen, 2009). LMWH can be classified according to their molecular weight into first generation and second generation, as show in table 1 (Hirsh et al, 2001;Vignoli et al, 2011).…”

“…These differences influence to their antiangiogenic potentials and the possible anticancer mechanism (Norrby, 2006). The main mechanism underling the antiangiogenic effect of the LMWHs is based on their interaction with the heparin-binding site of VEGF and bFGF and the subsequent inhibition of their cellular receptors (VEGFR and FGFR) (Bobek & Kovarik, 2004;Debergh et al, 2010;Gasowska et al, 2009;Mousa & Petersen, 2009). Norrby and Nordenhem investigated if dalteparin (Fragmin, 6kDa), epirubicin as an important chemotherapeutic agent or a combination of these two drugs modulated angiogenesis in vivo by rat mesentery assay (Norrby & Nordenhem, 2010).…”

“…TFPI is a heparin-binding protein. Particularly, LMWH suppress the activity of the TF and release of TFPI which appear to inhibit tumor growth (Amirkhosravi et al, 2003;Bobek & Kovarik, 2004;Gasowska et al, 2009;Kuczka et al, 2009;Mousa & Petersen, 2009;Vignoli et al, 2006). Recent studies demonstrated that the inhibition of angiogenesis through the TFPI release is dependent on the molecular size of the heparin used.…”