Upregulation and Activation of Stat6 Precede Vascular Smooth Muscle Cell Proliferation in Carotid Artery Injury Model

Abstract

Abstract-The role of signal transducers and activators of transcription (STAT) proteins in modulating proliferation and differentiation of various cell types in the hematopoietic system and the central nervous system has been well established. In contrast, the pathophysiological role of these proteins in vascular proliferative diseases has remained unproven, despite in vitro observations emphasizing the involvement of the STAT system in mediating vascular smooth muscle cell (VSMC) proliferation. On the basis of our previous observations demonstrating the occurrence of a specific modulation of Stat6 protein during the proliferative, migratory, and differentiation phases of the developing brain, we investigated whether Stat6 protein is present and modulated in arterial tissue challenged by perivascular injury. The time course of expression and localization of Stat6 after arterial injury was analyzed by immunohistochemistry, Western blot analysis, and confocal microscopy. Six hours after injury, the expression of Stat6 was markedly increased. This overexpression preceded the onset of VSMC proliferation and was downregulated starting from 7 days after injury, coincident with the decline of VSMC proliferation. Moreover, early after injury, Stat6 was predominantly localized at the nuclear level, denoting its functional activation. Conversely, Stat6 staining at later time points was largely cytosolic, suggesting silencing effects of this signaling pathway. These data indicate that Stat6 signaling may contribute to the modifications of gene expression underlying VSMC activation in the context of acute vascular proliferative diseases. [1][2][3][4][5][6] In normal arteries, VSMCs are in a fully differentiated, low proliferative rate phenotype; however, a number of growth factors or inflammatory cytokines elaborated by infiltrating leukocytes and activated intrinsic vascular cells can promote VSMCs to dedifferentiate and begin to replicate within the media, to migrate from the media into the intima, and to massively proliferate within the intima. 2,7,8 Changes in VSMC behavior induced by extracellular stimuli require the execution of a rapid and complex program of transcriptional events, which results in the emergence of VSMCs from quiescence (for a review see Reference 9). The nature of the molecular pathways specifically coupling the vascular injury stimuli to the VSMC dedifferentiation process is currently under intense investigation in an attempt to identify critical targets for interventional therapies. 10 -19 The quantitative and qualitative changes observed in VSMC gene expression during this transition involve, among others, the activation of distinct cytosolic signaling pathways. 9 A signaling cascade that has been correlated with mitogenic and pleiotropic functional responses induced by a variety of growth factors and cytokines involves the members of the Janus kinase (JAK) family of cytoplasmic tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) and the signal transducers and activators of transcription (STAT) pro...

STAT6 expression in glioblastoma promotes invasive growth

“…These findings are in agreement with reports by others, which suggest that STAT6 is involved in regulating the proliferation of hematopoietic cells [34,59], fibroblasts [60] and vascular smooth muscle cells [61], and that it is involved in facilitating metastasis of colon cancer cells [28] as well as migration of prostate cancer cells [62]. Suggested mechanisms through which STAT6 enhances cell proliferation include up-regulation of Cdk6, which facilitates cell cycle progression, and Myc, which up-regulates additional components of the cell cycle [58].…”

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

“…In this system, up-regulation of signal transducer and activator of transcription protein 6 following vessel injury in vascular smooth muscle cells correlated with the increased expression of the IL-4/IL-13 receptor ␣-chain and the platelet-derived growth factor-␤ receptor. Because signal transducer and activator of transcription protein 6 is involved in the induction of transcription of the IL-4 and IL-4R ␣-chain, this finding may indicate a possible autocrine loop in vascular smooth muscle cells after arterial injury involving IL-4 (42). A direct effect of IL-4 on the vasculature has also been demonstrated in a preclinical evaluation of recombinant human IL-4.…”

“…However, this potentially negative effect of IL-4 on CD8 ϩ T cell differentiation is irrelevant in our CD8 ϩ T cell-depleted system. Another possibility is that IL-4 could mediate the development of transplant arteriosclerosis via a direct effect on the vasculature, as suggested by a study of acute vascular proliferative disease in a carotid artery injury model (42). In this system, up-regulation of signal transducer and activator of transcription protein 6 following vessel injury in vascular smooth muscle cells correlated with the increased expression of the IL-4/IL-13 receptor ␣-chain and the platelet-derived growth factor-␤ receptor.…”

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

“…STAT6, which signals downstream of IL‐4 and IL‐13, is important for the differentiation of TH4 cells, nitric oxide generation and major histocompatibility complex (MHC) class II expression by macrophages (Bruns & Kaplan, 2006). Modulation of the proliferation of different cells including fibroblasts, hematopoietic cells, and vascular smooth muscle cells is the major role of STAT6 (Baetta et al, 2000; Kriebel, Patel, Nelson, Grusby, & LaRochelle, 1999). Thus, activated STAT6 has been found in patients with Hodgkin lymphomas, cutaneous T cell lymphomas, adult T cell leukemia/lymphomas, primary mediastinal large B‐cell lymphomas and prostate cancer (Bruns & Kaplan, 2006).…”