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Page 6 of 14 Heng et al. Vessel Plus 2023;7:31 https://dx.doi.org/10.20517/2574-1209.2023.97

Enclosing vein grafts with rigid external supports theoretically has the potential to reduce or eliminate wall
tension entirely. However, by limiting vessel expansion, the resulting mean shear stress may become higher
than in unstented grafts. In a study by Liao et al., ex-vivo pressurization of saphenous veins when supported
by poly-lactic-co-glycolic acid (PLGA) demonstrated that veins supported with external sheaths exhibited
pressure to cross-sectional area (CSA) relationships closely approximating that of the sheath alone, resulting
in a stress-strain curve intermediating between those of unsupported veins and those of native arteries
[Figure 2C] . With serial pressure testing of biodegradable PLGA sheaths, it was found that
[21]
circumferential stress and modulus gradually increased over a period of 12 days, corresponding to PLGA
degradation. Despite providing only partial and temporary mechanical support, biodegradable sheaths in
this study still resulted in a reduction in vein graft wall thickness by 12 days. These data, together with later
studies exploring remodeling benefits associated with oversized external stents, suggest that the therapeutic
mechanism of external vein graft supports likely involves a combination of biological factors beyond
hemodynamic modulation alone.

Vessel wall morphology
While many studies of external vein graft support generally report some degree of reduction in wall
thickening, the remodeling seen in distinct vessel wall layers may vary depending on the properties of the
particular stent applied. Overall, the biological response of vein grafts to external stenting is multifaceted
and involves changes in both matrix deposition and cell proliferation.

Medial hypertrophy
Across multiple sheath iterations in literature, external vein graft stenting is consistently reported to reduce
the thickening of the tunica media layer of grafted veins. In studies of PTFE sheaths applied to SVGs in
porcine carotid bypass surgery, the tunica media CSA was found to be twice as thick in unstented vs. stented
vein grafts. Additionally, while the internal elastic lamina remained unchanged at 4 weeks, the external
[18]
elastic lamina became more separated as a result of this hypertrophy . Although both stented and
unstented SVGs demonstrated increased matrix deposition in comparison to ungrafted saphenous veins,
cell densities did not differ significantly between the two groups at 1 and 6 months, suggesting that reduced
cell proliferation rather than decreased matrix deposition was responsible for the observed reductions in
medial hypertrophy. Supporting this hypothesis, PTFE-stented vein grafts have demonstrated absent PCNA
expression in the media alongside an increased presence of infiltrating microvessels, whereas unstented vein
grafts exhibited abundant PCNA expression with absent microvessels. Growth factor activity, particularly
that of PDGF, also appears to play a substantial role in the reduction of medial cell proliferation. In a study
by Mehta et al., they found widespread distribution of PDGF α and β receptor subunits in all vessel layers of
both stented and unstented SVGs, and observed decreased expression of specifically the PDGF-BB isoform
in stented vein grafts, with PDGF-AA expression remaining similar between two groups . Together, these
[19]
findings emphasize the importance of growth factor signaling and chemotaxis tunica media remodeling
following external vein graft stenting.

Neointimal thickening
Unlike the consistent reductions seen with medial thickening, studies of external vein graft stenting have
demonstrated mixed effects on the tunica intima. Although denuded endothelium at vein graft anastomotic
sites is fully restored within 2 weeks of grafting, cell proliferation continues to form a neointimal layer
consisting of axially and circumferentially oriented SMCs. In a study by Violaris et al., they reported that
external stenting with PTFE produced a two-fold increase in the intimal CSA of saphenous veins, essentially
neutralizing the concurrent reduction in medial thickness . Consequently, although the overall impact of
[15]
PTFE stenting on wall thickness was negligible, luminal encroachment was increased by stent grafts due to
restriction of the outer vessel diameter. In an effort to reduce luminal encroachment, subsequent research