Celine Luu

Background: Abdominal aortic aneurysms (AAAs) are defined as an enlargement of the abdominal aorta exceeding 30 mm or 1.5 times its normal diameter.^1,2 Currently, two surgical procedures for AAAs are endovascular aortic repair and open surgical repair (OSR). The latter involves opening the abdominal cavity and implanting a synthetic vascular graft made of polyethylene terephthalate or expanded polytetrafluoroethylene.³ The mortality rate of OSR for AAA is about 1-7% with complications such as minimal endothelialization, which can lead to eventual graft failure, thrombosis, neointimal hyperplasia, and/or stenosis.^3-5 Meanwhile, acellular tissue-engineered vessels (A-TEVs) are segments of previously living tissue that have been harvested and decellularized and can be functionalized with various bioactive materials, such as vascular endothelial growth factor (VEGF) and heparin. Furthermore, VEGF is able to enhance endothelialization while heparin reduces thrombosis, and VEGF is able to bind heparin as its coreceptor and participate in various signaling cascades.^7-9

Objective: In this narrative review, we explored the potential usage of ATEVs implanted with VEGF and heparin as an alternative solution to complications that can be seen with synthetic vascular grafts utilized in open surgical repair of abdominal aortic aneurysms.

Search Methods: A literature search was conducted using the PubMed and Web of Science databases to find articles published between 2017 to 2025. The following keywords were used individually or in combination: “abdominal aortic aneurysm”, “acellular tissue-engineered vessels”, “vascular endothelial growth factor”, “heparin”.

Results: In addition to accelerating endothelialization and reducing thrombosis, another study found that VEGF attenuates neointimal hyperplasia in ATEVs by modulating the local inflammatory response. This was seen by the increase in anti-inflammatory M2 macrophage CD206⁺ marker in models that utilized ATEVs infused with VEGF and heparin when compared with the control groups.¹⁰ Immobilized VEGF with heparin in ATEVs was also shown to capture endothelial cells from blood and promote endothelialization in another study, as seen by the high presence of CD144 marker for endothelial cells in the lumen of ATEVs containing VEGF and heparin. Moreover, the pro-inflammatory M1 macrophage marker CD38 was considerably low in ATEVs with heparin and VEGF, while the EGR2 marker for M2 macrophages was high in the lumen, which once again indicated an anti-inflammatory effect.⁶ In a third study, immobilized VEGF (iVEGF) was shown to capture monocytes circulating in blood with high specificity, and would differentiate into a mixed endothelial cell and macrophage phenotype, which would further develop into mature endothelial cells. Some indicating transcription factors for development of endothelial cells were GATA2 and ERG, which showed upregulation with VEGF-heparin ATEVs.¹¹ This could result in angiogenesis downstream via the signaling pathways once VEGF and heparin bind to VEGF receptors.⁸

Conclusion: In conclusion, ATEVs functionalized with VEGF and heparin may be a promising alternative to current synthetic vascular grafts on the market for various cardiovascular conditions, including AAAs. The advantages of VEGF-heparin ATEVs include reduction of thrombosis, modulation of inflammatory responses by reducing rejection and neointimal hyperplasia, and prevention of stenosis, a common complication with synthetic vascular grafts.^6,7,10 Nevertheless, further research must be done as current research has mainly focused on smaller diameter vessels, with only a handful of articles demonstrating VEGF-heparin ATEVs in larger animal models and on larger arteries.

Works Cited:

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2. Golledge J, Thanigaimani S, Powell JT, Tsao PS. Pathogenesis and management of abdominal aortic aneurysm. Eur Heart J. 2023;44(29):2682-2697. doi:10.1093/eurheartj/ehad386
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8. Chan SJ, Esposito E, Hayakawa K, et al. Vascular Endothelial Growth Factor 165-Binding Heparan Sulfate Promotes Functional Recovery From Cerebral Ischemia. Stroke. 2020;51(9):2844-2853. doi:10.1161/STROKEAHA.119.025304
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10. Xie X, Wu Q, Liu Y, et al. Vascular endothelial growth factor attenuates neointimal hyperplasia of decellularized small-diameter vascular grafts by modulating the local inflammatory response. Front Bioeng Biotechnol. 2022;10:1066266. Published 2022 Dec 20. doi:10.3389/fbioe.2022.1066266
11. Smith RJ Jr, Nasiri B, Kann J, et al. Endothelialization of arterial vascular grafts by circulating monocytes. Nat Commun. 2020;11(1):1622. Published 2020 Apr 1. doi:10.1038/s41467-020-15361-2