Abstract
Vascular procedures, such as stenting, angioplasty, and bypass grafting, often fail due to intimal hyperplasia (IH), wherein contractile vascular smooth muscle cells (VSMCs) dedifferentiate to synthetic VSMCs, which are highly proliferative, migratory, and fibrotic. Previous studies suggest MAPK-activated protein kinase 2 (MK2) inhibition may limit VSMC proliferation and IH, although the molecular mechanism underlying the observation remains unclear. We demonstrated here that MK2 inhibition blocked the molecular program of contractile to synthetic dedifferentiation and mitigated IH development. Molecular markers of the VSMC contractile phenotype were sustained over time in culture in rat primary VSMCs treated with potent, long-lasting MK2 inhibitory peptide nanopolyplexes (MK2i-NPs), a result supported in human saphenous vein specimens cultured ex vivo. RNA-Seq of MK2i-NP–treated primary human VSMCs revealed programmatic switching toward a contractile VSMC gene expression profile, increasing expression of antiinflammatory and contractile-associated genes while lowering expression of proinflammatory, promigratory, and synthetic phenotype–associated genes. Finally, these results were confirmed using an in vivo rabbit vein graft model where brief, intraoperative treatment with MK2i-NPs decreased IH and synthetic phenotype markers while preserving contractile proteins. These results support further development of MK2i-NPs as a therapy for blocking VSMC phenotype switch and IH associated with cardiovascular procedures.
Highlights
A common complication associated with angioplasty and vascular grafting procedures is intimal hyperplasia (IH), characterized by rampant vascular smooth muscle cell (VSMC) proliferation and abundant extracellular matrix (ECM) deposition, resulting in excessive neointimal formation, stenosis, and conduit failure [1,2,3]
The positively charged MK2 inhibitory peptide (MK2i) was electrostatically complexed with poly(propyl acrylic acid) (PPAA), a negatively charged polymer that potentiates intracellular bioavailability and activity of cationic cargoes [31, 32], in a 50 μM:5 μM MK2i/PPAA ratio, generating MK2i-nanopolyplexes (MK2iNPs)
Previous reports show that PPAA has no impact on cell viability in vitro [31] and in human saphenous vein (HSV) cultures [33]
Summary
A common complication associated with angioplasty and vascular grafting procedures is intimal hyperplasia (IH), characterized by rampant vascular smooth muscle cell (VSMC) proliferation and abundant extracellular matrix (ECM) deposition, resulting in excessive neointimal formation, stenosis, and conduit failure [1,2,3]. Current strategies to mitigate IH utilize antiproliferative drugs, such as the chemotherapeutic agent paclitaxel [4] or the mTOR inhibitor sirolimus [5], which are integrated into drug-eluting stents and angioplasty balloons for vascular wall delivery [6,7,8]. Even with these interventions in place, nearly half of all grafts and angioplasties require further intervention because of IH. Increasing evidence suggests that antiproliferative treatments alone may impede graft reendothelialization, contributing to late-stage thrombosis [9]. An increased understanding of the molecular mechanisms regulating VSMC phenotypic switching is needed
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