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Improving Vascular Regeneration Performance of Electrospun Poly(ε-Caprolactone) Vascular Grafts via Synergistic Functionalization with VE-Cadherin/VEGF

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Abstract

In vivo, vascular endothelial growth factor (VEGF) and vascular endothelial cadherin (VE-cadherin) co-regulate the dynamic organization of endothelial cells during vascular sprouting, balancing angiogenesis and vascular stability. In this study, a novel bioactive surface integrating human VE-cadherin-Fc and VEGF-Fc fusion proteins was innovatively developed for the modification of poly(ε-caprolactone) (PCL) small-caliber electrospun fibrous grafts (VE-cad/VEGF-PCL) to promote the regeneration of functional endothelium and improve the patency of artificial vascular grafts. These fusion proteins self-assembled on the PCL fibers through the hydrophobic binding of Fc domains, improving surface hydrophilicity while reducing the adhesion of fibrinogen. In vitro results showed that the VE-cadherin/VEGF surface upregulated the expression of endogenous VE-cadherin and synergistically activated the VE-cadherin/VEGFR2/FAK/AKT/ERK signal transduction, which facilitated the functioning of human umbilical vein endothelial cells (HUVECs). Moreover, the VE-cadherin/VEGF surface significantly enhanced cellularization and capillary formation, then subsequently accelerated the regeneration of functional endothelium and smooth muscle in the VE-cad/VEGF-PCL grafts in a rat abdominal aorta replacement model. Together, these results highlight the advantages of VE-cadherin/VEGF surface in enhancing rapid endothelialization of electrospun vascular grafts and provide new insights into the design of cross-activating biomaterials.

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Acknowledgements

The authors gratefully acknowledge financial support from the National Key R&D Program of China (2020YFA0710802), the National Natural Science Foundation of China (Grant No. 32071364, 82172106), the NCC Fund (NCC2020PY18), Tianjin “Project + Team” Key Training Foundation (XC202035), and China Postdoctoral Science Foundation (2022M711707).

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  1. Yan Zhang, Ke Xu and Dengke Zhi contributed equally to the work.

Authors and Affiliations

  1. The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China

    Yan Zhang, Ke Xu, Dengke Zhi, Mengyuan Qian, Kaizheng Liu, Qizhi Shuai, Zheng Qin, Jinghui Xie, Kai Wang & Jun Yang

  2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China

    Yan Zhang

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  1. Yan Zhang
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Supplementary file1 (DOCX 33 KB)

Supplementary file2 (DOCX 33 KB)

42765_2022_213_MOESM3_ESM.tif

Supplementary file3 Scratch-wound healing images of HUVECs cultured on the TC-PS, VE-cad-Fc, VEGF-Fc, and VE-cad/VEGF-Fc surfaces for 8 and 24 hours (TIF 20606 KB)

42765_2022_213_MOESM4_ESM.tif

Supplementary file4 Characterization of the VE-cadherin/VEGF interface on the PCL electrospun fibrous grafts. a Morphology of the electrospun fibrous grafts detected by SEM, b XPS spectra of electrospun fibrous grafts before and after functionalization, c Stability of hVE-cad-Fc and hVEGF-Fc proteins immobilized on the VE-cad/VEGF-PCL grafts were evaluated by ELISA (TIF 14604 KB)

42765_2022_213_MOESM5_ESM.tif

Supplementary file5 Evaluation of the cellularization and capillary formation of the VE-cadherin/VEGF functionalized PCL electrospun fibrous grafts after subcutaneous implantation. A Representative H&E staining of the explanted PCL, VE-cad-PCL, VEGF-PCL, and VE-cad/VEGF-PCL grafts, B Quantitative analysis of cellularization of explanted grafts, C The capillaries in the cellularization area were detected by immunofluorescent staining with vWF (green) antibody (arrow indicated), D Quantitative analysis of blood number in the explanted grafts, E Quantitative analysis of blood vessel density in the explanted grafts. Statistical significance was calculated by One-way ANOVA followed by Tukey’s test. The data were reported as mean ± SEM, n = 3. **Significant difference, P < 0.01; *Significant difference, P < 0.05; ns indicated no statistical differences (TIF 19782 KB)

42765_2022_213_MOESM6_ESM.tif

Supplementary file6 Color Doppler ultrasound evaluation of the PCL, VE-cad-PCL, VEGF-PCL, and VE-cad/VEGF-PCL electrospun fibrous grafts at the 4th week after implantation (TIF 946 KB)

Supplementary file7 (DOCX 18 KB)

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Zhang, Y., Xu, K., Zhi, D. et al. Improving Vascular Regeneration Performance of Electrospun Poly(ε-Caprolactone) Vascular Grafts via Synergistic Functionalization with VE-Cadherin/VEGF. Adv. Fiber Mater. 4, 1685–1702 (2022). https://doi.org/10.1007/s42765-022-00213-z

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