Work

Vascular Smooth Muscle Cell Migration and P70S6K: Key Players in Intimal Hyperplasia Development

Year: 2025

Type: article

Abstract: BACKGROUND: Vascular smooth muscle cell (VSMC) recruitment and activation by vessel injury cause intimal hyperplasia (IH) and restenosis. Drug-eluting stents releasing mTOR (mechanistic target of rapamycin) blockers (sirolimus, everolimus [EV]) improve surgery outcomes but exhibit nonspecific effects and poor efficacy in diseased vessels. Drug combinations targeting the multifactorial processes leading to IH could enhance efficacy and reduce toxicity. Our previous work showed that Kv1.3 channel blockers such as 5-(4-phenoxybutoxy)psoralen (PAP-1) prevented IH. Since Kv1.3 signaling works through the MEK/ERK pathway, we hypothesize that PAP-1 and EV combination could improve antirestenotic therapies. METHODS AND RESULTS: The effects of PAP-1, EV, and their combination on IH development were studied in vivo using a carotid ligation mouse model and ex vivo in organ culture of human vessels. Individually, both drugs inhibited vessel remodeling, but, surprisingly, their combination canceled these inhibitory effects. In primary human VSMCs cultures, the drug combination abolished the inhibition of cell migration but not cell proliferation, which was even potentiated. We uncovered a crosstalk between mTOR and MEK/ERK pathways in VSMCs, centered on P70S6K activation. P70S6K phosphorylation levels correlated with IH development, even reproducing the differences in EV response between diabetic and nondiabetic samples. CONCLUSIONS: VSMC migration, rather than proliferation, mirrors PAP-1 and EV effects on IH development in vessels. Critically, we identify VSMC P70S6K phosphorylation as a surrogate marker for IH progression. The nonmonotonic responses of P70S6K activation to pathway blockers suggest the existence of a crosstalk element functioning as an exclusive NOR logic gate providing new insights for IH prevention strategies.

Source: Journal of the American Heart Association

DOI: 10.1161/jaha.124.038358