Adhesion inhibition “in vitro” by heparin derivatives correlates with their activity on angiogenesis in mice

Abstract

Many diseases are dominated by an anomalous or excessive angiogenesis. Tumor growth and metastasis formation are also angiogenesis dependent. Control of angiogenesis would be of interest if safe and effective angiogenesis inhibitors would be available.Heparin play an important role in angiogenesis and early data showed very promising antiangiogenic effects especially in combination with steroids; unfortunately further studies did not confirm these good results.Moreover the bleeding risks and the need of parenteral administration, reduced the interest on heparin as angiogenesis modulator.In the last years various derivatives of heparin, with different pharmacokinetic and anticoagulant properties have been produced and some of them seems to have interesting antiangiogenic activities in experimental models [1,2].In order to characterize the action of heparin derivatives in the adhesion processes, our group Abstract Heparin (HEP) play an important role in angiogenesis. Inhibition of matrix degrading enzymes and binding to adhesion molecules are some of the interaction mechanism. The bleeding risk and the need of parenteral administration, restrict the therapeutic use of HEP as angiogenesis modulator; presently derivatives, with different pharmacokinetic and anticoagulant properties, are available. In this study the "in vitro" anti-adhesion activity, tested with PMNs and endothelial cells, was compared with the effect on angiogenesis, evaluated in Matrigel implanted mice. Some HEP derivatives, with low anticoagulant activity, showed a significant angiogenesis inhibition. A positive correlation between adhesion inhibition in vitro and anti-angiogenesis effect in vivo was found suggesting that the interaction with adhesion molecules by HEP derivatives play a relevant role in the angiogenesis control.

Heparan sulfate domains on cultured activated glomerular endothelial cells mediate leukocyte trafficking

“…21,50 Recently, we have shown that heparin, LMW heparins, and HS also interfere with the leukocyte-mGEnC-1 interaction under dynamic flow conditions, which mimics the in vivo situation more realistically than a static adhesion assay. 47 We now show that the blocking of N-and 6-O-sulfated HS domains on activated mGEnC-1, with specific anti-HS antibodies strongly reduced the number of rolling and firmly adhering leukocytes, while the average leukocyte rolling velocity increased.…”

Controlled release of 2, 3 desulfated heparin exerts its anti‐inflammatory activity by effectively inhibiting E‐selectin

“…Heparin belongs to the group of vertebrate GAGs and has been used as antithrombotic drug for more than six decades, but it also has many other biological activities. It has been proved to be an anticoagulant, anti‐inflammatory, antiproliferative, antiangiogenic and antimetastatic 2, 3. Both anti‐inflammatory and antimetastatic effects of heparin are assumed to be partly due to its selectin (adhesion molecule, which recruits blood cells to the activated endothelium) blocking capacity.…”

“…Among these polymers, natural polymers have gained special interest over synthetic polymers mainly because of better biocompatibility, degradation products being biocompatible (in contrast to some of the synthetic monomer), cost effectiveness, and bulk availability. Chitosan is a linear, randomly distributed binary heteropolysaccharide consisting of1–4–linked 2‐acetamido‐2‐deoxy‐β‐ D ‐glucose and 2‐amino‐2‐deoxy‐β‐ D ‐glucan units. It is derived by alkaline N ‐deacetylation of chitin obtained from marine crustaceans 10.…”

2-0, 3-0 Desulfated Heparin does not Affect Radiation Injury Induced Mortality but Reduces Radiation Combined Skin-burn Injury Induced Survival in Mice

“…Although heparin has been used as an antithrombotic drug for more than 60 years, it also has many other biological activities. It has been proved to be an anticoagulant, anti-inflammatory, antiangiogenic, antiproliferative and antimetastatic [16,17]. It has been reported that heparin can inhibit the activation of a variety of inflammatory cells [18,19].…”