The serine proteases of the intrinsic blood coagulation cascade are slowly neutralized by antithrombin (AT) 1 (reviewed in Ref. 1). This inhibition is secondary to the generation of 1:1 enzyme⅐AT complexes whose formation is dramatically enhanced by the mast cell product, heparin (2). Damus et al. (3) hypothesized that endothelial cell surface heparan sulfate proteoglycans (HSPGs) function in a similar fashion to accelerate coagulation enzyme inactivation by AT and therefore are responsible for the nonthrombogenic properties of blood vessels. We initially demonstrated that perfusion of the hind limbs of normal rodents and rodents deficient in mast cells with purified thrombin and AT leads to a greatly elevated rate of thrombin⅐AT complex formation and that the enzyme heparitinase as well as the natural heparin antagonist platelet factor 4 suppress the above acceleration (4, 5). We subsequently showed that cultured cloned bovine macrovascular and rodent microvascular endothelial cells synthesize both anticoagulant HSPG (HSPG act ) and nonanticoagulant HSPG (HSPG inact ) (6 -8). HSPG act bear glycosaminoglycan (GAG) chains that bind tightly to AT and accelerate thrombin⅐AT complex generation (6 -8).The biosynthesis of HSPG act requires generation of a core protein; assembly of a linkage region of four neutral sugars on specific serine attachment sites of the core protein; elongation of a GAG backbone composed of alternating N-acetylglu-
This model may be useful to evaluate new strategies in bone tissue engineering because the PMMA-induced membrane may help confine bone morphogenetic proteins, skeletal stem cells, or other agents to the defect cavity where they could be useful to enhance bone formation.
Proliferation of vascular smooth muscle cells (SMC) is postulated to be a key step in the pathogenesis of atherosclerosis or restenosis after vascular interventions such as angioplasty. Natural glycosaminoglycans, such as heparin and heparan sulfate, are known for their ability to inhibit SMC proliferation in vivo and in vitro. The antiproliferative activity of synthetic derivatized dextrans exhibiting heparin-like anticoagulant and anticomplement capacities have been investigated with rat aorta smooth muscle cells in culture. We report here that some derivatized dextrans grafted with benzylamide sulfonate moieties are potent antiproliferative agents for rat smooth muscle cell (SMC) in vitro. These synthetic polymers inhibit the SMC proliferation as well as heparin. The SMC growth inhibition is dose dependent, reversible and non-toxic. Highly anionic carboxylic dextrans are not capable of inhibiting the SMC growth, excluding a simple charge effect mechanism. Using fluorescent (DTAF) probes, we demonstrated that the synthetic antiproliferative polymers and heparin are internalized into the SMC. No binding or internalization was observed with native dextran devoid of antiproliferative capacity. We conclude that a suitable distribution of functional groups on the dextran backbone can simulate heparin activity in terms of antiproliferative capacity on SMC growth.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.