Neovasculogenic effect of 11,12-epoxyeicosatrienoic acid involves the Akt/eNOS signaling pathways in human endothelial progenitor cells

Hung-Chang Hung; Jia-Ning Syu; Che-Yi Chao; Shu-Ming Huang; Cheng-Chieh Lin; Mei-Due Yang; Shu-Yao Tsai; Feng-Yao Tang

doi:10.37796/2211-8039.1343

Neovasculogenic effect of 11,12-epoxyeicosatrienoic acid involves the Akt/eNOS signaling pathways in human endothelial progenitor cells

Biomedicine (Taipei). 2022 Sep 1;12(3):20-30. doi: 10.37796/2211-8039.1343. eCollection 2022.

Authors

Hung-Chang Hung^#¹, Jia-Ning Syu^#², Che-Yi Chao^#^{3

4}, Shu-Ming Huang^{5

6}, Cheng-Chieh Lin^{7

8

9}, Mei-Due Yang¹⁰, Shu-Yao Tsai³, Feng-Yao Tang²

Affiliations

¹ Department of Internal Medicine, Nantou Hospital, Ministry of Health and Welfare, Nantou City, 540, Taiwan, Republic of China.
² Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, 40402, Taiwan, Republic of China.
³ Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, 41354, Taiwan, Republic of China.
⁴ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, Republic of China.
⁵ Department of Nutrition, Nantou Hospital, Ministry of Health and Welfare, Nantou City, 540, Taiwan, Republic of China.
⁶ Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, 43302, Taiwan, Republic of China.
⁷ School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan, Republic of China.
⁸ Department of Family Medicine, China Medical University Hospital, Taichung, 40402, Taiwan, Republic of China.
⁹ Department of Healthcare Administration, College of Health Science, Asia University, Taichung, 41354, Taiwan, Republic of China.
¹⁰ Department of Surgery, China Medical University Hospital, Taichung, 40402, Taiwan, Republic of China.

^# Contributed equally.

Abstract

The 11,12-epoxy-eicosatrienoic acid (11,12-EET) is formed from arachidonic acid (AA) by cytochrome P450 2J2 (CYP 2J2) epoxygenase and function as an effector in blood vessels. Human endothelial progenitor cells (hEPCs), a preceding cell source for endothelial cells (ECs), involve in the vascular tissue repairing by postnatal neovasculogenesis. However, the effect of 11, 12-EET on hEPCs and neovasculogenesis is not well known. In the current study, we examined the function of 11, 12-EET in hEPCs-mediated neovasculogenesis by using tubular formation analysis, Western Blotting assay, immunofluorescence staining, flow cytometry analysis and zymogram analysis. The results suggest that 11, 12-EET significantly induces neovasculogenesis through the phosphorylation of phosphoinositide 3-kinase (PI3-K)/Akt, endothelial-nitric oxide synthase (e-NOS) and extracellular signal-regulated kinase 1/2 (ERK 1/2) signaling pathways. 11, 12-EET up-regulates the expression of cyclin D1, cyclin-dependent kinase 4 (CDK4) and nuclear factor kappa B (NF-κB) proteins. Moreover, 11, 12-EET augments the expression of VE-cadherin and CD31 proteins in hEPCs. 11, 12-EET also augmented Rac1/Rho A signaling cascades, cell migration and an up-regulation of matrix metalloproteinase (MMP) -2 and -9 proteins. These results demonstrate that 11, 12-EET exerts a significant function in the neovasculogenesis of hEPCs.

Keywords: 11; 12-Epoxyeicosatrienoic acid; Human endothelial progenitor cells; Neovasculogenesis; eNOS.