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Electroporation technique induced by high-voltage pulses has been successfully used to ablate tumor cells while preserving the function of normal blood vessels. Generally, the tumor blood vessels can provide a pathway to draw nutrients for tumor growth and contribute to invasion and metastasis, which is an obstacle to tumor treatment. The electroporation study of the endothelial cell, which is important in the vasculature microenvironment, is helpful to investigate the influence on both tumor and normal blood vessels. This study built a multicell-layer model of the vascular microenvironment to investigate the discriminative electroporation effect between normal and tumor blood vessels by high-frequency bipolar pulses (HFBPs) and monopolar pulses (MPs). The simulation results showed that both pore number and electroporation region in normal blood vessels are significantly lower than those in tumor blood vessels. The rich vascular smooth muscle cells existed in the normal blood vessels play a protective function for endothelial cells, compared with tumor blood vessels. However, the differences in pore number and electroporation region between normal and tumor blood vessels are gradually smaller with an increased electric field, which demonstrates that the electroporation pulse with higher intensity damages both normal and tumor blood vessels. HFBPs generate a weaker electroporation effect on both normal and tumor blood vessels than traditional MP. However, HFBPs are more suitable to electroporate tumor blood vessels, while preserving the normal blood vessels. Moreover, this study could also provide a multicell-layer model that can be used to analyze the cell electroporation effect in the vascular microenvironment. [ABSTRACT FROM AUTHOR]