Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation

Abstract

Mindin/spondin 2, an extracellular matrix (ECM) component that belongs to the thrombospondin type 1 (TSR) class of molecules, plays prominent roles in the regulation of inflammatory responses, angiogenesis and metabolic disorders. Our most recent studies indicated that mindin is largely involved in the initiation and development of cardiac and cerebrovascular diseases [Zhu et al. (2014) J. Hepatol. 60, 1046-1054; Bian et al. (2012) J. Mol. Med. 90, 895-910; Wang et al. (2013) Exp. Neurol. 247, 506-516; Yan et al. (2011) Cardiovasc. Res. 92, 85-94]. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expression was significantly down-regulated in platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) and wire injury-stimulated vascular tissue. Using a gain-of-function approach, overexpression of mindin in VSMCs exhibited strong anti-proliferative and anti-migratory effects on VSMCs, whereas significant suppression of intimal hyperplasia was observed in transgenic (TG) mice expressing mindin specifically in smooth muscle cells (SMCs). These mice exhibited blunted VSMC proliferation, migration and phenotypic switching. Conversely, deletion of mindin dramatically exacerbated neointima formation in a wire-injury mouse model, which was further confirmed in a balloon injury-induced vascular lesion model using a novel mindin-KO (knockout) rat strain. From a mechanistic standpoint, the AKT (Protein Kinase B)-GSK3β (glycogen synthase kinase 3β)/mTOR (mammalian target of rapamycin)-FOXO3A (forkhead box O)-FOXO1 signalling axis is responsible for the regulation of mindin during intimal thickening. Interestingly, an AKT inhibitor largely reversed mindin-KO-induced aggravated hyperplasia, suggesting that mindin-mediated neointima formation is AKT-dependent. Taken together, our findings demonstrate that mindin protects against vascular hyperplasia by suppression of abnormal VSMC proliferation, migration and phenotypic switching in an AKT-dependent manner. Up-regulation of mindin might represent an effective therapy for vascular-remodelling-related diseases.

Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

“…PI3K was demonstrated to be an intracellular signaling molecule, and shares catalytic activities that can activate the downstream molecules. PI3K is able to phosphorylate AKT protein to induce the expression of target genes [24, 25]. As reported, the PI3K/AKT signaling was involved in the regulation of different biological progression, involving cell growth, mitosis and apoptosis.…”

WISP1 overexpression promotes proliferation and migration of human vascular smooth muscle cells via AKT signaling pathway

“…Phosphorylated Akt activates various proteins involved in many cellular responses, including cell survival and growth promotion (Frame and Cohen, 2001). Glycogen Synthase Kinase-3α/β (GSK3α/β) is one of the major downstream targets of Akt involved in migration and proliferation of VSMCs (Shin et al, 2003;Zhu et al, 2015). In addition, cyclin D1 and Matrix Metalloproteinase 9 (MMP9) have been shown to regulate cell cycle and cell migration respectively, and play crucial roles in the development of vascular lesion (Park et al, 2015;Shin et al, 2003).…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…223 On the basis of gain-and loss-of-function experiments, we showed that Mindin has a strong inhibitory ability on the proliferation and migration of VSMCs post vascular injury, thereby suppressing intimal hyperplasia. Our further mechanistic studies suggested that the antiproliferative capacity of Mindin dependent on the inactivation of AKT−GSK3β/ mTOR−FOXO3A-FOXO1 signaling axis during intimal thickening.…”

“…Our further mechanistic studies suggested that the antiproliferative capacity of Mindin dependent on the inactivation of AKT−GSK3β/ mTOR−FOXO3A-FOXO1 signaling axis during intimal thickening. 223 Whether IRFs involved in the Mindin-regulated neointima formation is unknown.…”