Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis

Abstract

BackgroundAbnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood.MethodsWound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE−/− mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas.ResultsIGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE−/− mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima.ConclusionsOur data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0477-3) contains supplementary material, which is available to authorized users.

The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications

“…In this sense, a significant increase in the expression of IRA in the aorta of 24-week-old ApoE −/− mice has been described, which may favour the proatherogenic actions of IGF-II. In addition, gene expression of IRA, IGF-IR, and IGFs has been reported to be markedly increased in the middle layer, mainly composed of VSMCs, of human aortas with early atherosclerotic lesions [ 106 ] ( Figure 3 ).…”

“…It has been established that the IR isoforms and the IGF-IR have a differential role in early and advanced atherosclerosis, since they favour atherogenesis in the initial stages while preventing instability and rupture of atherosclerotic plaques [ 106 ]. In more advanced phases, where local IGF-II action might prevent plaque weakening by promoting the proliferation of VSMCs in the intima [ 105 ], there is a decrease in the IRA/IRB ratio and less IGF-II actions, and as a consequence, it would be favouring the apoptosis and instability of atherosclerotic lesions.…”

Noncoding RNAs as therapeutic targets in atherosclerosis with diabetes mellitus

“…Insulin‐like growth factor (IGF) plays an important role in the progression of vascular disease in diabetic condition by promoting the proliferation of VSMCs . An intragenic lncRNA, IRAIN, from insulin growth factor 1 receptor (IGF‐1R) gene locus is involved in the regulation of expression for IGF‐1R expression.…”

“…Insulin-like growth factor (IGF) plays an important role in the progression of vascular disease in diabetic condition by promoting the proliferation of VSMCs. 55 and p300 play an important role in the regulation of p53 activity.…”

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

“…This signaling pathway is also frequently used to determine the invasiveness and motility of tumors (Wallace et al 2013). The insulin like growth factor 1 (IGF-1) molecule is another regulator various functions, including the frequently reported effect on cell migration for cardiac stem cells (O’Neill et al 2016), as well as vascular smooth muscle cells (Beneit et al 2016). Similar to some other factors described above, IGF-1 is extensively involved in tumor invasion (Le Coz et al 2016).…”