Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation

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. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expressions were significantly downregulated 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, while significant suppression of intimal hyperplasia was observed in transgenic (TG) mice expressing mindin specifically in 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 rat strain. From mechanistic standpoint, the AKT−GSK3β/mTOR−FOXO3A–FOXO1 signaling axis is responsible for the regulation of mindin during intimal thickening. Interestingly, an AKT inhibitor largely reversed mindin-KO-induced aggravated h...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research