Acute Elution of TGFβ2 Affects the Smooth Muscle Cells in a Compliance-Matched Vascular Graft.

Abstract

Transforming growth factor beta 2 (TGFβ2) is a pleiotropic growth factor that plays a vital role in smooth muscle cell (SMC) function. Our prior <i>in vitro</i> work has shown that SMC response can be modulated with TGFβ2 stimulation in a dose dependent manner. In particular, we have shown that increasing concentrations of TGFβ2 shift SMCs from a migratory to a synthetic behavior. In this work, electrospun compliance-matched and hypocompliant TGFβ2-eluting tissue engineered vascular grafts (TEVGs) were implanted into Sprague Dawley rats for 5 days to observe SMC population and collagen production. TEVGs were fabricated using a combined computational and experimental approach that varied the ratio of gelatin:polycaprolactone to be either compliance matched or twice as stiff as rat aorta (hypocompliant). TGFβ2 concentrations of 0, 10, 100 ng/mg were added to both graft types (<i>n</i> = 3 in each group) and imaged <i>in vivo</i> using ultrasound. Histological markers (SMC, macrophage, collagen, and elastin) were evaluated following explanation at 5 days. <i>In vivo</i> ultrasound showed that compliance-matched TEVGs became stiffer as TGFβ2 increased (100 ng/mg TEVGs compared to rat aorta, <i>p</i> < 0.01), while all hypocompliant grafts remained stiffer than control rat aorta. <i>In vivo</i> velocity and diameter were also not significantly different than control vessels. The compliance-matched 10 ng/mg group had an elevated SMC signal (myosin heavy chain) compared to the 0 and 100 ng/mg grafts (<i>p</i> = 0.0009 and 0.0006). Compliance-matched TEVGs containing 100 ng/mg TGFβ2 had an increase in collagen production (<i>p</i> < 0.01), general immune response (<i>p</i> < 0.05), and a decrease in SMC population to the 0 and 10 ng/mg groups. All hypocompliant groups were found to be similar, suggesting a lower rate of TGFβ2 release in these TEVGs. Our results suggest that TGFβ2 can modulate <i>in vivo</i> SMC phenotype over an acute implantation period, which is consistent with our prior <i>in vitro</i> work. To the author's knowledge, this is the first <i>in vivo</i> rat study that evaluates a TGFβ2-eluting TEVG. Impact statement TGFβ2 affects the SMCs in a vascular graft.