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PubMed2003

Hyaluronan synthase in trabecular meshwork cells.

BACKGROUND/AIMS: Hyaluronan is present in the trabecular meshwork where it is involved in the pathophysiology of aqueous outflow environment. In this study, the expression and regulation of hyaluronan synthase (HAS), which is the enzyme synthesising hyaluronan, in trabecular meshwork cells were investigated. METHODS: Cultured bovine trabecular meshwork cells (BTMCs) were used. HAS expression in BTMCs was examined by RT-PCR. The effects of transforming growth factor beta (TGF-beta) and platelet derived growth factor BB (PDGF-BB) on HAS expression in BTMCs were examined by quantitative RT-PCR. The HAS2 expression by TGF-beta and PDGF-BB at the protein level was also confirmed immunohistochemically. The production of hyaluronan from BTMCs was detected by high performance liquid chromatography (HPLC). RESULTS: Three HAS isoforms were expressed in BTMCs at the mRNA level. Among HAS isoforms, only the expression of HAS2 mRNA was increased by the administration of TGF-beta or PDGF-BB. HAS2 upregulation by these growth factors was also confirmed at the protein level. Further, hyaluronan production from BTMCs was stimulated by TGF-beta or PDGF-BB. CONCLUSION: Expression of HAS in trabecular meshwork may maintain the hyaluronan content in the aqueous outflow pathway. Its production is regulated by TGF-beta and PDGF-BB. The regulation of the expression of HAS in trabecular meshwork might be useful for modulating the aqueous outflow environment.

Animals↗
PubMed2005

Thrombospondin 1 acts as a strong promoter of transforming growth factor beta effects via two distinct mechanisms in hepatic stellate cells.

BACKGROUND AND AIMS: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth factor beta (TGF-beta) but little is known of the expression patterns and functions of TSP-1 in liver cells. We therefore analysed if and how TSP-1 acts on TGF-beta during fibrogenesis. METHODS AND RESULTS: Using reverse transcription-polymerase chain reaction, we demonstrated that hepatocytes from normal liver expressed no TSP-1 mRNA whereas Kupffer cells and sinusoidal endothelial cells did. TSP-1 mRNA and protein were detected in quiescent and activated cultured hepatic stellate cells (HSC) and TSP-1 expression was highly inducible by platelet derived growth factor BB (PDGF-BB) and, to a lesser extent, by tumour necrosis factor alpha in activated HSC. Furthermore, addition of PDGF-BB directly led to enhanced TGF-beta mRNA expression and a TSP-1 dependent increase in TGF-beta/Smad signalling. Using either a peptide specifically blocking the interaction of TSP-1 with latent TGF-beta or antibodies against TSP-1 not only abrogated activation of latent TGF-beta but also reduced the effects of the active dimer itself. CONCLUSIONS: Our data suggest that TSP-1 expression is important for TGF-beta effects and that it is regulated by the profibrogenic mediator PDGF-BB in HSC. Furthermore, the presence of TSP-1 seems to be a prerequisite for effective signal transduction by active TGF-beta not only in rat HSC but also in other cell types such as human dermal fibroblasts.

Animals↗
PubMedDate not supplied

Glycosaminoglycans from two human malignant mesothelioma cell lines: determination, distribution, and effect of platelet-derived growth factor on their synthesis.

The synthesis and distribution of glycosaminoglycans (GAGs) were studied in two human malignant mesothelioma cell lines: one with fibroblast-like morphology and the other with epithelial differentiation. Analyses using highly sensitive high-pressure liquid chromatography techniques and agarose gel electrophoresis showed that these cells produce not only hyaluronan (HA) but also galactosaminoglycans (GalAGs, chondroitin sulfate and (or) dermatan sulfate) and heparan sulfate (HS). In both cell lines most of the HA (87-90%) and GalAGs (57-66%) are secreted into the extracellular matrix. Although HS is mainly bound to the cell surface in fibroblast-differentiated cells (75%), in epithelial type cells only 40% occurs in the cell-associated fraction. The amounts of secreted GAGs are 6- to 8-fold higher in epithelial than in fibroblast-like mesothelioma cultures. In cells with the fibroblast phenotype, the beta-homodimer of platelet-derived growth factor (PDGF) in a concentration of 1.5 ng/mL stimulates HA and GalAG synthesis 5-fold and that of HS 10-fold, whereas higher concentrations suppress this stimulatory effect. The stimulatory effect, observed at low concentrations of this growth factor, was completely blocked by the addition of antibodies against this factor. In epithelially differentiated cells, the production of all GAGs was suppressed after addition of this factor, even at low concentrations. We therefore suggest that mesothelioma cells can produce GAGs, the synthesis of which is dependent on the presence and concentration of PDGF beta-homodimer. The differences between the two cell lines regarding the effect of this growth factor on GAG synthesis indicates that the regulation of this synthesis is complex, other factors also being important.

Becaplermin↗
PubMed2002

B2 receptor activation reduces Erk1 and Erk2 phosphorylation induced by insulin-like growth factor-1, platelet-derived growth factor-BB, and high glucose in rat isolated glomeruli.

Several experimental data document an activation of the mitogen-activated protein kinases Erk1 and Erk2 by bradykinin (BK), an agonist of the kinin B2 receptor (B2R). In contrast, other reports showed an inhibitory modulation of mitogenesis by BK. Therefore, we explored in the isolated glomeruli the effect of B2R activation on the signaling of insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB), and high glucose (HG), three factors that are believed to be involved in the development of glomerulosclerosis via the phosphorylation of Erk1 and Erk2. We observed that the activation of B2R negatively modulates the phosphorylation of Erk1 and Erk2 induced by IGF-1, PDGF-BB, and HG in the glomerulus. These effects are consistent with the hypothesis of a protective role for BK in the kidney during development of glomerulosclerosis and renal pathologies associated with a hyperproliferative state.

Animals↗
PubMed1995

The cystine-knot growth-factor superfamily.

Four recent crystal structures of growth factors--nerve growth factor, transforming growth factor-beta, platelet-derived growth factor, and human chorionic gonadotropin--from four separate superfamilies revealed that these proteins are structurally related and share a common overall topology. These proteins have very little sequence homology, but they all have an unusual arrangement of six cysteines linked to form a "cystine-knot" conformation. The active forms of these proteins are dimers, either homo- or heterodimers. Despite the overall topological similarity between the monomers, the interfaces used to form the dimer are in each case quite different. Because the surfaces used for dimer formation are mostly hydrophobic, the uniqueness of each dimer accounts for the lack of sequence homology and raises questions about the effectiveness of reverse sequence fitting in this kind of structure as a predictor of structural homology.

Becaplermin↗
PubMed2002

Insulin inhibits PDGF-directed VSMC migration via NO/ cGMP increase of MKP-1 and its inactivation of MAPKs.

In this study, we examined the role of insulin in the control of vascular smooth muscle cell (VSMC) migration in the normal vasculature. Platelet-derived growth factor (PDGF) increased VSMC migration, which was inhibited by pretreatment with insulin in a dose-dependent manner. Insulin also caused a 60% decrease in PDGF-stimulated mitogen-activated protein kinase (MAPK) phosphorylation and activation. Insulin inhibition of MAPK was accompanied by a rapid induction of MAPK phosphatase (MKP-1), which inactivates MAPKs by dephosphorylation. Pretreatment with inhibitors of the nitric oxide (NO)/cGMP pathway, blocked insulin-induced MKP-1 expression and restored PDGF-stimulated MAPK activation and migration. In contrast, adenoviral infection of VSMCs with MKP-1 or cGMP-dependent protein kinase Ialpha (cGK Ialpha), the downstream effector of cGMP signaling, blocked the activation of MAPK and prevented PDGF-directed VSMC migration. Expression of antisense MKP-1 RNA prevented insulin's inhibitory effect and restored PDGF-directed VSMC migration and MAPK phosphorylation. We conclude that insulin inhibition of VSMC migration may be mediated in part by NO/cGMP/cGK Ialpha induction of MKP-1 and consequent inactivation of MAPKs.

Animals↗
PubMed2005

The postnatal rat aorta contains pericyte progenitor cells that form spheroidal colonies in suspension culture.

Pericytes play an important role in modulating angiogenesis, but the origin of these cells is poorly understood. To evaluate whether the mature vessel wall contains pericyte progenitor cells, nonendothelial mesenchymal cells isolated from the rat aorta were cultured in a serum-free medium optimized for stem cells. This method led to the isolation of anchorage-independent cells that proliferated slowly in suspension, forming spheroidal colonies. This process required basic fibroblast growth factor (bFGF) in the culture medium, because bFGF withdrawal caused the cells to attach to the culture dish and irreversibly lose their capacity to grow in suspension. Immunocytochemistry and RT-PCR analysis revealed the expression of the precursor cell markers CD34 and Tie-2 and the absence of endothelial cell markers (CD31 and endothelial nitric oxide synthase, eNOS) and smooth muscle cell markers (alpha-smooth muscle actin, alpha-SMA). In addition, spheroid-forming cells were positive for NG2, nestin, PDGF receptor (PDGFR)-alpha, and PDGFR-beta. Upon exposure to serum, these cells lost CD34 expression, acquired alpha-SMA, and attached to the culture dish. Returning these cells to serum-free medium failed to restore their original spheroid phenotype, suggesting terminal differentiation. When embedded in collagen gels, spheroid-forming cells rapidly migrated in response to PDGF-BB and became dendritic. Spheroid-forming cells cocultured in collagen with angiogenic outgrowths of rat aorta or isolated endothelial cells transformed into pericytes. These results demonstrate that the rat aorta contains primitive mesenchymal cells capable of pericyte differentiation. These immature cells may represent an important source of pericytes during angiogenesis in physiological and pathological processes. They may also provide a convenient supply of mural cells for vascular bioengineering applications.

Actins↗
PubMed2006

Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells.

Smooth muscle cell (SMC) differentiation is an essential component of vascular development and these cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. SMCs are not terminally differentiated and possess the ability to modulate their phenotype in response to changing local environmental cues. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMC with particular focus on examination of processes that contribute to the repression of SMC marker genes. We discuss the environmental cues which actively regulate SMC phenotypic switching, such as platelet-derived growth factor-BB, as well as several important regulatory mechanisms required for suppressing expression of SMC-specific/selective marker genes in vivo, including those dependent on conserved G/C-repressive elements, and/or highly conserved degenerate CArG elements found in the promoters of many of these marker genes. Finally, we present evidence indicating that SMC phenotypic switching involves multiple active repressor pathways, including Krüppel-like zinc finger type 4, HERP, and ERK-dependent phosphorylation of Elk-1 that act in a complementary fashion.

Animals↗
PubMed2006

Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters.

A hallmark of smooth muscle cell (SMC) phenotypic switching is suppression of SMC marker gene expression. Although myocardin has been shown to be a key regulator of this process, the role of its related factors, MKL1 and MKL2, in SMC phenotypic switching remains unknown. The present studies were aimed at determining if: 1) MKL factors contribute to the expression of SMC marker genes in cultured SMCs; and 2) platelet-derived growth factor-BB (PDGF-BB)-induced repression of SMC marker genes is mediated by suppression of MKL factors. Results of gain- and loss-of-function experiments showed that MKL factors regulated the expression of single and multiple CArG [CC(AT-rich)(6)GG]-containing SMC marker genes, such as smooth muscle (SM) alpha-actin and telokin, but not CArG-independent SMC marker genes such as smoothelin-B. Treatment with PDGF-BB reduced the expression of CArG-containing SMC marker genes, as well as myocardin expression in cultured SMCs, while it had no effect on expression of MKL1 and MKL2. However, of interest, PDGF-BB induced the dissociation of MKL factors from the CArG-containing region of SMC marker genes, as determined by chromatin immunoprecipitation assays. This dissociation was caused by the competition between MKL factors and phosphorylated Elk-1 at early time points, but subsequently by the reduction in acetylated histone H4 levels at these promoter regions mediated by histone deacetylases, HDAC2, HDAC4, and HDAC5. Results provide novel evidence that PDGF-BB-induced repression of SMC marker genes is mediated through combinatorial mechanisms, including downregulation of myocardin expression and inhibition of the association of myocardin/MKL factors with CArG-containing SMC marker gene promoters.

Actins↗
PubMed1994

Involvement of protein kianse C and Ca2+ in angiotensin II-induced mitogenesis of cardiac fibroblasts.

Angiotensin (ANG) II has been previously shown to stimulate proliferation of neonatal rat cardiac fibroblasts via AT1 receptors. Here we conducted studies to assess involvement in this process of two second messengers linked to AT1 receptors, protein kinase C (PKC) and Ca2+. Several findings argue against a dominant role for PKC in ANG II-induced mitogenesis: 1) [Sar1]ANG II, which produced a modest, transient increase in PKC activity, was equally effective in inducing thymidine incorporation into DNA in PKC-depleted cells, whereas the effect of platelet-derived growth factor (PDGF)-BB on thymidine incorporation was reduced to the level observed with [Sar1]ANG II; 2) phorbol 12-myristate 13-acetate (PMA), a potent PKC stimulator, was ineffective in stimulating thymidine incorporation; and 3) PKC downregulation or the highly specific PKC inhibitor, compound 3, eliminated PMA-induced mitogen-activated protein (MAP) kinase activity but did not affect comparable increases induced by [Sar1]ANG II or PDGF-BB. Increased intracellular Ca2+ may be sufficient to account for [Sar1]ANG II-induced MAP kinase activity because ionomycin also increased MAP kinase activity and chelation of intracellular Ca2+ eliminated [Sar1]ANG II-induced activity in PKC-depleted fibroblasts. However, Ca2+ chelation did not prevent [Sar1]ANG II-induced MAP kinase activity in non-PKC-depleted fibroblasts. Thus ANG II can activate MAP kinase in cardiac fibroblasts by either Ca(2+)- or PKC-dependent pathways, and whereas the full effect of PDGF-BB on thymidine incorporation and cell proliferation requires a phorbol ester-sensitive PKC, the hyperplastic growth effect of ANG II does not.

Angiotensin II↗
PubMed1995

Isoform-specific induction of the low-density lipoprotein receptor gene by platelet-derived growth factor.

We investigated the effect of recombinant platelet-derived growth factor (PDGF) isomers on low-density lipoprotein (LDL) receptor gene expression and compared this with two indexes of cell growth response: expression of the immediate early gene c-myc and the rate of DNA synthesis. In human skin fibroblasts and NIH 3T3 cells, the PDGF-BB homodimer was more effective in inducing the LDL receptor gene and cell growth response compared with the PDGF-AA homodimer. The second messenger pathways utilized by PDGF receptors for enhancing LDL receptor gene response could, however, be dissociated from those utilized for enhancing c-myc gene response and were insensitive to inhibitors of tyrosine phosphorylation. Inhibition of tyrosine kinase activity inhibited c-myc gene response to PDGF-BB at 10(-8) M but had little effect on LDL receptor gene response. Such inhibition increased expression of the LDL receptor gene in the presence of the PDGF-AA isomer. Our results indicate that the response of the LDL receptor gene to PDGF isoforms reflects cellular growth response. However, different transduction pathways are utilized for PDGF activation of the c-myc and LDL receptor genes in mesenchymal cells.

3T3 Cells↗
PubMed1995

The mitogenic effect of platelet-derived growth factor in human hepatic stellate cells requires calcium influx.

Platelet-derived growth factor (PDGF) is a key mitogen for hepatic stellate cells (HSC) and has been shown to be implicated in liver tissue repair and fibrogenesis. In this study the relationship between PDGF-induced intracellular Ca2+ concentration ([Ca2+]i) increase and mitogenesis in cultured human HSC was evaluated. In high-density cell cultures (80-90% subconfluence), PDGF induced a significant increase in [Ca2+]i, characterized by a short-lasting peak phase, which was followed by a long-lasting plateau phase. The plateau phase was abolished in the absence of extracellular Ca2+. However, in low-density cell cultures (30-40% subconfluence), the plateau phase was absent or markedly less pronounced. In parallel sets of experiments, PDGF was significantly less effective in inducing mitogenesis in low-density cell cultures than in high-density cell cultures and was totally ineffective in the absence of extracellular Ca2+. These results suggest that 1) spatial and time dynamics of PDGF-induced [Ca2+]i increase are dependent on cell density and 2) PDGF-induced mitogenesis requires extracellular Ca2+ influx.

Becaplermin↗
PubMed1996

Differential long-term regulation of MEK and of p42 MAPK in rat glomerular mesangial cells.

Constitutive stimulation of the mitogen-activated protein kinase (MAPK) activator MAPK/ERK kinase (MEK) is sufficient to promote long-term events such as cell differentiation, proliferation, and transformation. To evaluate a possible mechanism for the chronic regulation of MEK and p42 MAPK, we studied the long-term effects of fetal bovine serum (FBS), the G protein-coupled receptor agonist endothelin-1 (ET-1), and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor BB (PDGF BB) on MEK and p42 MAPK in glomerular mesangial cells (GMC). FBS, ET-1, and PDGF BB led to a time-dependent increase in MEK-1 mRNA and protein expression without altering p42 MAPK mRNA and protein levels. FBS also induced MEK-1 mRNA expression in diverse cell types, including NIH/3T3 fibroblasts, A7r5 vascular smooth muscle cells, and Chinese hamster ovary cells. In GMC, cycloheximide inhibited MEK-1 mRNA induction but stimulated p42 MAPK mRNA expression in the absence and presence of FBS, ET-1, or PDGF. The FBS-induced increase in MEK-1 mRNA was accompanied by a sustained enhancement of MEK activity, as assessed by the ability of immunoprecipitated p45 MEK to activate recombinant p42 MAPK and hence phosphorylate myelin basic protein, and p42 MAPK activity. We conclude that, in GMC, MEK-1 acts like a delayed-early gene and that it can be chronically induced at the mRNA and protein level.

Animals↗
PubMed1996

Endothelin and PDGF enhance arachidonic acid release and DNA synthesis in vascular smooth muscle cells.

Intracellular signaling mechanisms affected by endothelin (ET), a hypertrophic agonist, and platelet-derived growth factor (PDGF)-BB, a proliferative agonist, in vascular smooth muscle cells were examined. PDGF-BB was a potent mitogen compared with untreated cultures, stimulating both [3H]thymidine incorporation and cell number. In contrast, ET was a poor mitogen, enhancing [3H]thymidine incorporation but not cell number. Simultaneous ET and PDGF-BB treatment was significantly more effective than either agonist alone at stimulating both [3H]thymidine uptake and cell number. Although either ET or PDGF-BB alone stimulated arachidonic acid release, phosphoinositide hydrolysis, protein kinase C activation, PDGF receptor phosphorylation, and mitogen-activated protein kinase activity, of these effectors, only arachidonic acid release was further enhanced by simultaneous ET and PDGF-BB treatment. These results link proliferative and hypertrophic signal transduction pathways in these cells and suggest that arachidonic acid or its metabolites mediate the observed effects of ET on PDGF-BB-stimulated vascular smooth muscle cell proliferation.

Animals↗
PubMed1997

Endothelial cell-conditioned medium downregulates smooth muscle contractile protein expression.

Smooth muscle cells (SMC) within atherosclerotic lesions proliferate and exhibit phenotypic modulation, but the contribution of vascular endothelium to this process is poorly understood. Our aim was to examine the effects of endothelial cell-conditioned medium (ECCM) on vascular SMC growth and differentiation. Rat aortic ECCM stimulated a ninefold increase in [3H]thymidine incorporation and downregulated smooth muscle-specific myosin heavy chain and alpha-actin synthesis in rat aortic SMC. These effects were not inhibited by antibodies to platelet-derived growth factor (PDGF)-BB or PDGF-AB or with a PDGF beta-receptor subunit. Treatment with PDGF-BB (at a concentration found in ECCM), PDGF-AA, basic fibroblast growth factor, endothelin-1, or transforming growth factor-beta did not reproduce these effects. The ECCM activities were sensitive to heat and trypsinization, were >30 kDa in molecular mass, and bound weakly to heparin-Sepharose. Our data indicate that cultured endothelial cells produce a factor(s) that downregulates contractile protein expression in SMC, which may contribute to SMC dedifferentiation and proliferation.

Actins↗
PubMed1997

G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras.

The binding of vasoactive peptides to their respective G protein-coupled receptors has been implicated in the pathogenesis of vascular smooth muscle cell proliferation, leading to the development of hypertension, arteriosclerosis, and restenosis after vascular injury. We previously showed that the cytosolic tyrosine kinase pp60c-src is crucial for angiotensin II (ANG II)-induced activation of the protooncogene p21ras. Therefore, we investigated the role of pp60c-src and p21ras in rat aortic smooth muscle cell proliferation induced by several G protein-coupled receptors. ANG II, endothelin-1, or thrombin increased cell proliferation and DNA synthesis. Electroporation of anti-pp60c-src antibodies into cells abolished proliferation in response to these G protein-coupled receptor ligands but not in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, electroporation of anti-p21ras antibody completely blocked DNA synthesis and cell proliferation in response to ANG II, endothelin-1, thrombin, and PDGF-BB. Our data indicate that the pp60c-src tyrosine kinase is necessary and specific for vascular smooth muscle cell proliferation and DNA synthesis in response to G protein-coupled receptors but not classic growth factor receptors.

Angiotensin II↗
PubMed1997

Regulation of vascular angiotensin II receptors by EGF.

After vascular endothelial injury, angiotensin II (ANG II) plays a role in the resulting hypertrophic response, and expression of epidermal growth factor (EGF) is enhanced. Therefore, we tested the possibility that EGF regulates vascular ANG II action and receptor expression. Incubation of cultured aortic vascular smooth muscle cells (VSMC) with EGF (or basic fibroblast growth factor but not platelet-derived growth factor isoforms) resulted in concentration-dependent (1-50 ng/ml EGF), time-dependent (>8 h), and reversible decreases in ANG II surface receptor density. For example, a 50% reduction was observed after exposure to 50 ng/ml EGF for 24 h. Incubation of cultured VSMC with 50 ng/ml EGF for 24 h resulted in a 77% reduction in ANG II-stimulated inositol phosphate formation. EGF not only prevented but also reversed ANG II receptor upregulation by 100 nM corticosterone. The specific tyrosine kinase inhibitor tyrphostin A48 (50 microM) reduced EGF-stimulated thymidine incorporation and EGF-stimulated phosphorylation of mitogen-activated protein kinase but did not prevent EGF from reducing ANG II receptor density. Neither pertussis toxin (100 ng/ml) nor downregulation of protein kinase C by phorbol myristate acetate (100 nM for 24 h) prevented EGF from reducing ANG II receptor density. In summary, EGF is a potent negative regulator of vascular ANG II surface receptor density and ANG II action by mechanisms that do not appear to include tyrosine phorphorylation, pertussis toxin-sensitive G proteins, or phorbol ester-sensitive protein kinase C. The possibility that EGF shifts the cell culture phenotype to one that exhibits reduced surface ANG II density cannot be eliminated by the present studies.

Angiotensin II↗
PubMed1998

Ets-1 is an early response gene activated by ET-1 and PDGF-BB in vascular smooth muscle cells.

Ets-1 is a transcription factor that activates expression of matrix-degrading proteinases such as collagenase and stromelysin. To study the control of ets-1 gene expression in rat vascular smooth muscle cells (VSMC), cells were exposed to factors known to regulate VSMC migration and proliferation. Platelet-derived growth factor-BB (PDGF-BB), endothelin-1 (ET-1), and phorbol 12-myristate 13-acetate (PMA) induced a dose-dependent expression of ets-1 mRNA. These effects were abrogated by inhibition of protein kinase C (PKC) by H-7 or chronic PMA treatment. Ets-1 mRNA was superinduced by PDGF-BB and ET-1 in the presence of cycloheximide. The chelation of intracellular Ca2+ by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester and the depletion of endoplasmic reticulum intracellular Ca2+ concentration ([Ca2+]i) by thapsigargin inhibited PDGF-BB- and ET-1-induced ets-1 mRNA, whereas ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid had no effect. However, [Ca2+]i release alone was not sufficient to increase ets-1 mRNA. Forskolin blocked ET-1-, PDGF-BB-, and PMA-induced ets-1 mRNA, as well as inositol phosphate formation, consistent with an effect through impairment of PKC activation. Inhibitors of ets-1 gene expression, such as H-7 and herbimycin A, inhibited the ET-1 induction of collagenase I mRNA. We propose that ets-1 may be an important element in the orchestration of matrix proteinase expression and of vascular remodeling after arterial injury.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗