In a second set of experiments on the microcirculation of LLC-1 carcinoma and BFS-1 fibrosarcoma, platelet-endothelial interactions were assessed in response to endothelial stimulation by calcium ionophore A23187. Calcium ionophore A23187 increases intracellular calcium concentration and thereby induces the release of adhesion molecules vWF and P-selectin from endothelial cell-specific Weibel-Palade bodies sparing endothelial integrity. The secretion of Weibel-Palade bodies from endothelial cells plays a central role in wound healing, coagulation, inflammation, and ischemia-reperfusion injury. In addition, angiogenic growth factor VEGF induces the secretion of Weibel-Palade bodies and adhesion molecule presentation. Hence, tumor cells might influence adhesion molecule expression in microvessels .
The application of calcium ionophore A23187 did not affect platelet-endothelial interaction in BFS-1 fibrosar-coma, and only a slight increase in platelet rolling was detected in microvessels of the LLC-1 carcinoma. However, in subcutaneous venules of tumor-free tissue, platelet rolling increased significantly (Figure 4). Platelet adherence was only occasionally seen following superfusion with calcium ionophore. The results indicate that tumor microvessels do not express sufficient amounts of vWF and P-selectin in response to stimulation with calcium ionophore A23187. In respect to the stimulus used, this phenomenon can be attributed to the reduced or missing secretion of adhesion molecules from endothelial Weibel-Palade bodies .
Figure 4 Calcium ionophore A23187 induces platelet rolling favorably in normal and less in tumor microvessel. Superfusion of tumor tissues with calcium ionophore A23187 (20 ||M) over 15 minutes causes a twofold increase of rolling platelets in LLC-1 (gray bars) and exerts no effects on BFS-1 (hatched bars) on day 14 after tumor cell implantation. In contrast, the treatment of tumor-free preparations resulted in a threefold increase of rolling platelets in postcapillary venules of controls (open bars) on corresponding days to tumor groups after chamber preparation. n = 6 experimental animals per group, *p < 0.05 versus controls, #p < 0.05 versus baseline (Kruskal-Wallis test and Wilcoxon test).
Immunohistological studies on vWF and P-selectin stored in Weibel-Palade bodies of endothelial cells describe a granular staining pattern in the microcirculation of differentiated tissues . In tumor microvessels, however, vWF expression appears to be extremely heterogeneous. Immunohistological techniques showed reduced or even absent staining for vWF alternating with areas highly positive for vWF. In follicular thyroid cancer, vWF was not detectable, whereas it was highly significant in normal thyroid tissue. A similar immunohistological pattern has been found for P-selectin expression within the tumor microcirculation. The distribution pattern of vWF and P-selectin was never associated with angiogenic processes.
Hence, immunohistological studies disclose that vWF and P-selectin storage in Weibel-Palade bodies of endothe-lial cells is reduced in tumor microvessels. This might be a consequence of Weibel-Palade body exocytosis due to sustained stimulation by angiogenic growth factors and cytokines preventing redistribution and regeneration of vWF and P-selectin into their intracellular storage granules. Furthermore, angiogenic growth factors prevent protein synthesis of adhesion molecules that are required for interactions of platelets as well as of leukocytes with the microvascular endothelium. Distribution of Weibel-Palade bodies within the tumor microcirculation seems to depend on tumor type and species. Weibel-Palade bodies may be completely missing in the microvasculature of some tumors.
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