Regulation of SM22α expression by arginine vasopressin and PDGF-BB in vascular smooth muscle cells

Abstract

This process involves coordinated changes in expression of multiple SM-specific genes. In cultured VSMC, arginine vasopressin (AVP) increases and PDGF decreases expression of SM ␣-actin (SMA), the earliest marker of SM cells (SMC). However, it is unknown whether these agents regulate other SM genes in a similar fashion. SM22␣ appears secondary to SMA during development and is also a marker for SMC. This study examined the regulation of SM22␣ expression by AVP and PDGF in cultured VSMC. Levels of SM22␣ mRNA and protein were increased by AVP and suppressed by PDGF. Consistent with these changes, AVP increased SM22␣ promoter activity, whereas PDGF inhibited basal promoter activity and blocked AVP-induced increase. Activation of both JNK and p38 MAPK pathways was necessary for AVP-mediated induction of SM22␣ promoter. Expression of constitutively active Ras produced similar suppressions on SM22␣ promoter activity as PDGF. Signaling relayed from PDGF/Ras activation involved Raf, or a protein that competes for this site, Ral-GDS, and phosphatidylinositol 3-kinase activation. Truncational analysis showed that the proximal location of three CArG boxes in the promoter was sufficient for AVP stimulation. Mutations in this CArG box reduced basal and AVP-stimulated promoter activity without effecting PDGF suppression. Overexpression of serum response factor enhanced basal and AVP-stimulated promoter activity but had no effect on PDGF-BB-induced suppression. These data indicate that AVP and PDGF initiate specific signaling pathways that control expression of multiple SM genes leading to phenotypic modulation.

Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells

“…Mutations in the CArG boxes of SM-specific genes inhibit expression of SM-markers during development, 5,6,14 and regulation by hormonal factors in cultured VSMC. 12,13,31,32 Phenotypic remodeling in mature vessels is regulated by local environmental cues including humoral factors, cell-cell and cell-matrix interactions, mechanical stresses, and inflammatory stimuli. Our laboratory has observed the convergence of signaling from both differentiating and dedifferentiating signals on SRF transactivation.…”

“…AVP-induced increases in gene expression require c-jun amino terminal kinase and p38 MAP kinases, whereas PDGF-induced suppression is mediated by Ras, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. 1,[11][12][13] The promoters of these SM-genes contain common regulatory elements, specifically multiple CArG boxes, which have been shown to bind the MCM1, agamous, deficiens, serum response factor (MADS) box transcription factor, serum response factor (SRF). 14,15 Many SM-genes contain multiple CArG boxes in the proximal region of their promoter.…”

Transgelin: An actin-binding protein and tumour suppressor

“…Prolonged incubation of cells with TGF-␤ induces formation of stress fibres, inhibiting cell migration and invasion. Activation of the Ras-MEK-ERK-myc signalling pathway antagonises TGF-␤ inhibition of cell motility, and suppresses transgelin expression (Shields et al, 2002), as does immortalisation and transformation by RNA and DNA viruses (Kaplan-Alberquerque, Garat, Van Putten, & Nemenoff, 2003;Lawson et al, 1997). Expression of transgelin is decreased in breast and colon cancers (Shields et al, 2002;Wulfkuhle et al, 2002) and in prostate cancer (Yang et al, 2007;ourselves, unpublished data).…”

Aortic smooth muscle cell alterations in mice systemically exposed to arsenic

“…It is known that local production of growth factors such as PDGF is involved in SMC phenotype switching, SMC migration, and vessel wall reorganization [11,12]. Previous studies indicated that PDGF-BB treatment significantly decreased production of SM-specific markers, such as SM α-actin, smooth muscle myosin heavy chain (SMMHC), and SM22α, in SMCs [10,24,29,30]. Our data showed that arsenic exposure-induced SMC alteration is accompanied by upregulation of Egr-1 and PDGF, suggesting that Egr-1/PDGF signaling is involved in early arsenic-mediated structural changes of the aorta.…”