Vascular smooth muscle cells in intimal hyperplasia, an update

Abstract

Arterial occlusive disease is the leading cause of death in Western countries. Core contemporary therapies for this disease include angioplasties, stents, endarterectomies and bypass surgery. However, these treatments suffer from high failure rates due to re-occlusive vascular wall adaptations and restenosis. Restenosis following vascular surgery is largely due to intimal hyperplasia. Intimal hyperplasia develops in response to vessel injury, leading to inflammation, vascular smooth muscle cells dedifferentiation, migration, proliferation and secretion of extra-cellular matrix into the vessel's innermost layer or intima. In this review, we describe the current state of knowledge on the origin and mechanisms underlying the dysregulated proliferation of vascular smooth muscle cells in intimal hyperplasia, and we present the new avenues of research targeting VSMC phenotype and proliferation.

Keywords: intimal hyperplasia; neointima; peripheral artery disease; restenosis; smooth muscle cells; vascular remodeling; vascular surgery.

SCHEME 1

Pathways involved in the VSMC contractile phenotype. The contractile phenotype of VSMC is ensured by the coordinated activity of transcription factors SRF, MYOCD and MTRFs. Canonical TGFβ signaling through Smad2/3 promotes the activity of the SRF, MYOCD complex. YAP/TAZ degradation downstream of cytoskeleton-mediated signaling in relation to extracellular interactions with neighboring cells and the ECM maintains the contractile phenotype. FOXO4 degradation via Akt2 activity is also important to maintain the contractile phenotype. EC-derived NO and H₂S ensure maintenance of the contractile phenotype by various mechanisms. PTEN also maintains the contractile phenotype via inhibition of PI3K activity and direct binding to SRF. Ang II and Ang-1-7 binding to the AT2R and Mas receptor potentiate the benefits of TGFβ signaling. Ang II, angiotensin II; AT2R, Ang II receptor 2; SRF, serum response factor; MYOCD, myocardin; MTRFs, myocardin-related transcription factors; FAK, focal adhesion Kinase; YAP, Yes-associated protein; TAZ, Transcriptional coactivator with PDZ-binding motif; GPCR, G protein coupled receptor; TGFβ, transforming growth factor beta; ECM, extra cellular matrix; FOXO4, Forkhead Box O4; PI3K, phosphoinositide 3-kinase; IRS1, insulin receptor 1; IGF-1R, isulin-like growth factor receptor 1; α-SMA, alpha smooth muscle actin; SM-MHC, smooth muscle myosin heavy chain; SM22α, smooth muscle 22 alpha; SMAD, Suppressor of Mothers Against Decapentaplegic 2; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue; NO, nitric oxide; H₂S, hydrogen sulfide; mTORC1, mammalian target of rapamycin complex 1; MEK1/2, mitogen-activated ERK kinase; ERK1, 2, extracellular signal-regulated kinase; IGF-1, insulin like growth factor 1; IGF-1R, IGF-1 receptor; IRS1, insulin receptor 1.

SCHEME 2

Pathways involved in the loss of the VSMC contractile phenotype. Downstream of PDGF-BB and cytokines, activation of the MAPK pathway drives disruption of the SRF/MYOCD/MTRFs complex. Non-cononical TGFβ signaling further promotes the MAPK activity and inhibition of Smad signaling. ERK mediated phosphorylation of MRTFs also prevents nuclear translocation. KLF4 and TCF members Elk1 and TCF21 displace MYOCD and induce SRF-dependent transcription of early response growth genes. mTORC1 activation promotes protein synthesis and cell growth, and Akt2 inhibition, which leads to FOXO4 translocation to the nucleus to sequester MYOCD. ECM and cell-cell interaction remodeling leads to YAP/TAZ translocation to the nucleus to promote the expression of genes associated with proliferation via the TEAD transcription factors. MAPK and TLR4 activation stimulates the NF-κB signaling and expression of pro-inflammatory genes. Activation of GPCR signaling via Ang II binding to the AT1R, thromboxane A2 or endothelin-1 binding to the ET-1R activates deleterious MAPK and ROCK signaling, and further transactivates TGFβ and growth factor signaling. AT1R, Ang II receptor 1; SRF, serum response factor MYOCD, myocardin; MTRFs, myocardin-related transcription factors; FAK, focal adhesion Kinase; YAP, Yes-associated protein; TAZ, Transcriptional coactivator with PDZ-binding motif; GPCR, G protein coupled receptor; TGFβ, transforming growth factor beta; ECM, extra cellular matrix; FOXO4, Forkhead Box O4; PI3K, phosphoinositide 3-kinase; mTORC1, mammalian target of rapamycin complex 1; KLF4, kruppel-like factor 4; TEAD, transcription enhancer activation domain; TCF21, ternary complex factor 21; Elk-1, ETS domain-containing protein-1; ET-1R, endothelin-1 receptor; ERK1/2, extracellular-signal-regulated kinase; MEK1/2, mitogen-activated ERK kinase; PDGF-BB, platelet-derived growth factor.

SCHEME 3

Phenotypic transition of VSMCs in intimal hyperplasia. Upon vessel injury, EC dysfunction and death triggers an early inflammatory response leading to recruitment of platelets and immune cells, which secrete factors facilitating reprogramming of VSMC toward proliferating and secreting VSMCs. Recent evidence suggest that a few VSMC first transition to an intermediate MSC-like phenotype before clonal expansion of clusters of cells secreting ECM components and osteo and chondrocyte markers. While important in the context of atherosclerosis, it is unclear whether VSMC transdifferentiate in pro-inflammatory macrophage-like cells during IH. Additionally, myofibroblasts probably arise from adventitial fibroblast and resident or circulating progenitor cells. EC, endothelial cells; VSMC, vascular smooth muscle cells, MSC, mesenchymal stem cells; Sca1, Stem cells antigen-1 (Ly6a); Klf4, kruppel-like factor 4; Lgals3, galectin 3.