The Synergistic Effects of Prostaglandin E1 and Copper on Angiogenesis
New blood vessel formation, or angiogenesis, is a critical process in both physiological and pathological conditions. Tumor growth in particular is highly dependent on the development of a new vascular network to supply nutrients and oxygen. Some evidence suggests that the acquisition of angiogenic capacity by tissues normally devoid of this ability may indicate a high risk of neoplastic transformation.
The morphogenesis of new capillaries involves a sequence of events including endothelial cell mobilization, proliferation, canalization, and production of a supporting stroma. However, the precise conditions necessary to trigger this angiogenic cascade are not fully understood. Here presents the findings of experiments conducted using the rabbit corneal assay that shed light on two key events in the angiogenic process: the production of prostaglandin E1 (PGE1) and the increased concentration of copper in the target tissue.
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The study utilized male and female New Zealand White rabbits as the animal model. Some rabbits were placed on a copper-deficient diet to examine the role of this essential mineral in angiogenesis. Tumor interstitial fluid (TIF) was collected from MTW9A and Walker carcinomas transplanted in female Wistar-Furth rats.
Surgical procedures were performed under anesthesia. In some experiments, rabbits were treated with the cyclooxygenase inhibitor indomethacin to block prostaglandin synthesis. Corneal implants were used to assess angiogenic responses.
The TIF from the MTW9A and Walker carcinomas exhibited strong angiogenic activity in the rabbit corneal assay. Analysis revealed that the TIF was rich in E-type prostaglandins, with PGE1 being the most potent inducer of new blood vessel growth compared to PGE2, PGI2, and PGF2α.
Neoplastic fibroblasts also elicited a robust angiogenic response in the cornea. However, this response was abrogated in rabbits pre-treated with indomethacin, suggesting a critical role for prostaglandin synthesis in the angiogenic process.
Interestingly, copper levels were found to increase in the cornea during PGE1-induced neovascularization. Furthermore, copper-deficient rabbits were unable to mount an angiogenic response in the corneal assay. The copper-binding protein ceruloplasmin was also observed to be angiogenic at high doses, but this effect was lost in indomethacin-treated animals.
The results of this study indicate that the production of PGE1 and the mobilization of copper in the target tissue are two key events that occur during angiogenesis. The data suggest that angiogenesis is the culmination of a series of interdependent processes, with PGE1 synthesis and copper availability representing critical steps.
The finding that copper deficiency abrogates the angiogenic response underscores the importance of this trace mineral in the formation of new blood vessels. Copper may play a role in endothelial cell proliferation, extracellular matrix remodeling, or other aspects of the angiogenic cascade.
Collectively, these results provide valuable insights into the complex mechanisms underlying angiogenesis, a process that is fundamental to both physiological and pathological conditions. Further elucidation of these pathways may inform the development of novel therapeutic strategies targeting aberrant angiogenesis, such as in cancer.
References
- Ziche, M., Jones, J., et al. Role of prostaglandin E1 and copper in angiogenesis. Journal of the National Cancer Institute. 1982, 69(2), 475-482.
- Bryan, B. A., & D'amore, P. A. What tangled webs they weave: Rho-GTPase control of angiogenesis. Cellular and molecular life sciences. 2007, 64, 2053-2065.
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