Biphasic Growth Research Articles

Pax-6 Expression in Posthatch Chick Retina during and Recovery from Form-Deprivation Myopia

The expression of Pax-6 in fully-differentiated chick retina remains largely confined to the amacrine and ganglion cell layers. In the developing posthatch chick retina, Pax-6 expression shows a biphasic pattern; a decrease by posthatch day 17 followed by a steady increase in the adult eye. Interestingly, we find that this biphasic expression of Pax-6 is reflected in the biphasic growth pattern of the posthatch chick eye, which is disrupted by form-deprivation myopia (FDM). We have now examined the pattern of Pax-6 accumulation in 3-day-old chick eyes subjected to 2 weeks of FDM followed by 2 weeks of recovery from FDM. Quantitative RT-PCR (with a homologous internal control) revealed that after 2 weeks of occlusion the contralateral non occluded eyes, the occluded eyes and the normal nonexperimental chick eyes did not show any drastic changes in the number of Pax-6 transcripts. The data obtained suggests that the contralateral eye does not represent a ‘normal’ control eye; similar but nonidentical changes are seen, at the molecular level, in both the contralateral and the occluded eyes. Comparisons with the control nonexperimental animals, however, are meaningful. Even after 2 weeks of recovery under normal light conditions, the occluded eyes do not seem to reach the same level of Pax-6 expression (number of molecules per mg tissue) as seen in normal control eyes, suggesting that exposure of the posthatch chick eye to FDM impedes developmental progression that normally culminates in emmetropia.

Optimal life histories and food web position: linkages among somatic growth, reproductive investment, and mortality

Life history variation among 60 Ontario populations of lake trout (Salvelinus namaycush), walleye (Sander vitreus), cisco (Coregonus artedii), and yellow perch (Perca flavescens) is presented and interpreted using a biphasic model of individual growth that specifically accounts for the significant shift in energy allocation that accompanies sexual maturity. We show that the constraints imposed on life history variation by the character of the biphasic growth model are such that optimal life histories will exhibit associations among growth parameters, reproductive investment, and mortality that are largely consistent with associations evident in both our data set and earlier empirical studies; the von Bertalanffy growth parameter k varies with reproductive investment, and both k and investment vary with adult mortality. Our analysis suggests that within a food web, life history parameters will shift in a predictable fashion with the decreases in mortality expected as one moves from primary consumers up toward top predators. This expectation is supported by the differences in life history parameters that we observe between the two top predators in our data set (lake trout and walleye) and the two mid-trophic level consumers (cisco and yellow perch).

Cutaneous Myoepithelial Carcinoma in a Neonate

A 27‐day‐old female neonate presented with a bleeding growth on the abdomen. The clinical differential diagnosis included pyogenic granuloma and hemangioma. Histology shows an ulcerated, spindled and round cell tumor in the dermis with ill‐defined margins that invade the subcutaneous fat. The tumor exhibits a biphasic growth pattern with plump spindled cells arranged in fascicles, as well as epithelioid cells arranged in sheets. Some cells show plasmacytoid features. The tumor cells have pleomorphic, vesicular nuclei. Single cell necrosis and mitotic activity is prominent. Myxoid and chondroid stromal changes are focally seen. Immunohistochemical stains show strong positivity for S100 protein, calponin, and, focally, AE1/AE3. Portions of the both the spindled and epithelioid cell components show staining with EMA. Desmin and MSA stains were negative. The tumor does not stain for CD 31, CD 30, CD 45, CD 20, CD 34, CK 20, MART‐1, or HMB45. These histologic features are consistent with a cutaneous myoepithelial carcinoma. Cutaneous myoepitheliomas are rare tumors of myoepithelial cells which surround eccrine and apocrine glands. While most myoepitheliomas are benign, tumors with high mitotic activity may have a risk for recurrence or metastasis. This is, to our knowledge, the youngest patient described with myoepithelial carcinoma.

Hormetic Effects of Hormones, Antihormones, and Antidepressants on Cancer Cell Growth in Culture: In Vivo Correlates

Evidence is presented that the ability of hormones and antihormones to cause biphasic (hormetic) proliferative responses in cancer cells in vitro correlates with a similar effect of these substances in humans with cancer. Certain antidepressants also produce biphasic growth responses of cancer cells in vitro and stimulate cancer growth in rodents, correlating with an increased risk of breast and other cancers in some, but not all, epidemiological studies assessing early and/or late cancer incidence in patients on antidepressant drugs. The observation that certain drugs with biphasic effects on cancer cell growth in vitro may also produce an “up–down” effect on cancer growth in humans supports Calabrese's suggestion that the concept of the hormetic dose response must be taken seriously by toxicologists and regulators.

Human Metapneumovirus Persists in BALB/c Mice despite the Presence of Neutralizing Antibodies

Human metapneumovirus (HMPV) has emerged as an important human respiratory pathogen causing upper and lower respiratory tract infections in young children and older adults. Recent epidemiological evidence indicates that HMPV may cocirculate with respiratory syncytial virus, and HMPV infection has been associated with other respiratory diseases. In this study, we show that BALB/c mice are susceptible to HMPV infection, the virus replicates in the lungs with biphasic growth kinetics in which peak titers occur at days 7 and 14 postinfection (p.i.), and infectious HMPV can be recovered from lungs up to day 60 p.i. In addition, we show that genomic HMPV RNA can be detected in the lungs for >/=180 days p.i. by reverse transcription-PCR; however, neither HMPV RNA nor infectious virus can be detected in serum, spleen, kidneys, heart, trachea, and brain tissue. Lung histopathology revealed prevalent mononuclear cell infiltration in the interstitium beginning at day 2 p.i. and peaking at day 4 p.i. which decreased by day 14 p.i. and was associated with airway remodeling. Increased mucus production evident at day 2 p.i. was concordant with increased bronchial and bronchiolar inflammation. HMPV-specific antibodies were detected by day 14 p.i., neutralizing antibody titers reached >/=6.46 log(2) end-point titers by day 28 p.i., and depletion of T cells or NK cells resulted in increased HMPV titers in the lungs, suggesting some immune control of viral persistence. This study shows that BALB/c mice are amenable for HMPV studies and indicates that HMPV persists as infectious virus in the lungs of normal mice for several weeks postinfection.

Rectal adenocarcinoma with choriocarcinomatous differentiation: Clinical and genetic aspects

Nongestational choriocarcinomas are rare tumors. In the gastrointestinal tract, they are characterized by a biphasic tumor growth with separated areas of adenocarcinomatous and choriocarcinomatous differentiation. We here report a case of a combined adenocarcinoma-choriocarcinoma of the rectum. The tumor showed an aggressive clinical behavior with metastasis to the liver and lungs. A transient partial remission was achieved after 4 cycles of cisplatinum, etoposide, and ifosfamide chemotherapy, with normalization of serum β-human chorionic gonadotropin levels. At this time, viable residual choriocarcinoma cells were found in surgically resected lung metastasis. The patient succumbed 8 months after initial diagnosis to a rapid abdominal relapse. We used comparative genomic hybridization (CGH) and fluorescence in situ hybridization to elucidate the genetic relationship of adenocarcinoma and choriocarcinoma in this neoplasm. We found genetic changes characteristic for colorectal adenocarcinomas, a loss of chromosomal regions 8p21-pter as well as 18q21-pter, and a gain of 5p and 20q, in both tumor parts. This provides evidence for the common origin of both components. A differential pattern of additional genetic changes suggests a clonal evolution from a common ancestor cell. In contrast to findings from a comparative study on a choriocarcinoma of the renal pelvis, we did not find an amplification of the germ cell cancer-associated chromosomal region 12p11.2-p12.1 in the areas of choriocarcinoma but found instead a loss of Xp11.3-pter. To our knowledge, this is the first report of a CGH comparision of the adenocarcinomatous and choriocarcinomatous tumor parts in a nongestational choriocarcinoma of the gastrointestinal tract.

Immunohistochemical expression of CD10 antigen in uterine adenosarcoma

Uterine adenosarcoma (UAS) is microscopically characterized by a biphasic growth pattern. By definition, the epithelial component is benign, whereas the stromal component typically has the appearance of a low-grade sarcoma, usually an endometrial stromal sarcoma. CD10 acts by reducing cellular response to peptide hormones and is currently regarded as a specific marker for endometrial stromal tumors. In this international multicenter study, we further explored CD10 immunoreactivity in 30 UASs. We encountered CD10 positivity of the sarcomatous component in 18/20 (90%) of UASs, in five of eight (63%) of UASs with sarcomatous overgrowth as well as in both cases of recurrent UAS. The epithelial component stained negative in all cases. These findings suggest that CD10 can be used to differentiate UAS from cellular leiomyoma, or in case endometrial stromal cells exhibit muscle differentiation. Furthermore, CD10 positivity in recurrent UAS might guide the pathologist toward an endometrial stromal origin.

Isolation and characterization of a novel sphingomonad capable of growth with chrysene as sole carbon and energy source

A bacterial strain able to grow in pure culture with chrysene as sole added carbon and energy source was isolated from PAH-contaminated soil after successive enrichment cultures in a biphasic growth medium. Initially, growth occurred in the form of a biofilm at the interface between the aqueous and non-aqueous liquid phases. However, after a certain time, a transition occurred in the enrichment cultures, with growth occurring in suspension and a concomitant increase in the rate of chrysene degradation. The strain responsible for chrysene degradation in these cultures, named Sphingomonas sp. CHY-1, was identified by 16S rDNA sequencing as a novel sphingomonad, the closest relative in the databases being Sphingomonas xenophaga BN6 T (96% sequence identity). Both these strains clustered with members of the genera Sphingobium and Rhizomonas, but could not be categorically assigned to either genus. Sphingomonas sp. CHY-1 was characterized in terms of its growth on chrysene and other PAH, and the kinetics of chrysene degradation and 14C-chrysene mineralization were measured. At an initial chrysene concentration of 0.5 g l −1 silicone oil, and an organic/aqueous phase ratio of 1:4, chrysene was 50% degraded after 5 days incubation and 97.5% degraded after 35 days. The protein content of cultures reached a maximum value of 11.5 μg ml −1 aqueous phase, corresponding to 92 mg g −1 chrysene. 14C-labelled chrysene was 50% mineralized after 6–8 weeks incubation, 10.7% of the radioactivity was incorporated into cell biomass and 8.4% was found in the aqueous culture supernatant. Sphingomonas sp. CHY-1 also grew on naphthalene, phenanthrene and anthracene, and naphthalene was the preferred substrate, with a doubling time of 6.9 h.

Cranial ontogeny of otariid seals

Over 2000 otariid skulls were measured for a morphometric study of cranial ontogeny in fur seals and sea lions. Few interspecific differences in cranial ontogeny were observed in the Otariidae, with only minor differences in rates of growth. Sexual dimorphism was significant in all otariids but was more apparent in the larger species. Female otariids of each species showed monophasic development in all characteristics, whereas males expressed monophasic growth for some characters and biphasic growth for others. Biphasic development in skulls of male otariids occurred well after physical maturity had been reached, usually at a suture index of 27. The rate of development varied between skull characters; components relating to the nervous system completed growth well before the rest of the skull, whereas those related to feeding, respiration and vocalisation developed in synchrony with the overall growth of total skull length. Sutures of the calvaria, or braincase, were the first to show partial closure and those uniting the facial bones were usually the last to fuse. As with the calvaria, the orbits and otic capsules developed quickly, suggesting a need for good hearing and vision early in independent postnatal life. Development of the rostral and palatal regions required significantly longer to complete growth.

Quand, comment et pourquoi réaliser une imagerie d’un anévrisme de l’aorte abdominale ?

Usually atherosclerotic in origin, aneurysms of the abdominal aorta (AAA) tend to involve the infrarenal aorta. Their biphasic exponential growth pattern, initially slow then accelerated, results in a risk of rupture. Surgical management is recommended for aneurysm diameters of 45-50mm or for growth rates more than 5mm in 6 months. Imaging is useful for detection and follow-up of nonsurgical aneurysms, presurgical evaluation of aneurysms, and postsurgical follow-up. Frequently asymptomatic, AAA frequently is an incidental finding at the time of abdominal US. The size of the aneurysm sac, the presence of a neck and the size of the iliac arteries are assessed at the time of initial US detection. US is sufficient for follow-up of small aneurysms. Cross sectional imaging evaluation is necessary when surgery is contemplated. Readily available, multidetector row CT scanners with advanced image post-processing capabilities provide all the necessary information prior to surgical or endovascular management: evaluation of the aneurysm sac and neck, iliac and visceral arteries, and adjacent organs. Angiography with graduated catheters remains sometimes indicated. MR angiography provides results similar to CT but is less readily available and is usually reserved for patients with contraindication to iodinated contrast material. While follow-up imaging after surgical management is seldom performed, it is mandatory after endovascular management and includes KUB, Doppler US and CT or MR angiography.

Glycerol Metabolism of Lactobacillus rhamnosus ATCC 7469: Cloning and Expression of Two Glycerol Kinase Genes

Lactobacillus rhamnosus ATCC 7469 was able to grow in glycerol as the sole source of energy in aerobic conditions, producing lactate, acetate, and diacetyl. A biphasic growth was observed in the presence of glucose. In this condition, glycerol consumption began after glucose was exhausted from the culture medium. Glycerol kinase activity was detected in L. rhamnosus ATCC 7469, a characteristic of microorganisms which catabolize glycerol in aerobic conditions. Genetic analysis revealed that this strain possesses two glycerol kinase genes: gykA and glpK, that encode for two different glycerol kinases GykA and GlpK, respectively. The glpK geneis associated in an operon with α-glycerophosphate oxidase (glpO) and glycerol facilitator (glpF) genes. Transcriptional analysis revealed that only glpK is expressed when L. rhamnosus was grown on glycerol.

Growth kinetics of porcine lymphatic organs during early postnatal life.

During the critical early postnatal period, the development of lymphatic organs, being the major structural components of the immune system, progresses rapidly. In this context, the growth kinetics and growth rates of Peyer's patches, tonsilla veli palatini, lymphnodes (lc. mesentericum craniale and lc. bronchale), spleen and thymus were investigated in German landrace piglets from birth until 2 weeks of age. The weight of all these organs increased faster than body weight but regression analysis revealed remarkable differences in growth kinetics and growth rates. The lymphoepithelial organs (Peyer's patches, tonsilla veli palatini) had low growth rates at birth ( approximately 10%/day) that increased continuously until 2 weeks, while lymphnodes and spleen exhibited constant high growth rates ( approximately 40%/day). Small intestinal lymphnodes alone showed biphasic growth kinetics which could be attributed to colostrum absorption. The growth kinetics of the thymus included a point of inflexion at the end of the first week. The differences in growth kinetics and growth rates are discussed with regard to their immunobiological relevance.

Overexpression of groESL in Clostridium acetobutylicum results in increased solvent production and tolerance, prolonged metabolism, and changes in the cell's transcriptional program.

DNA array and Western analyses were used to examine the effects of groESL overexpression and host-plasmid interactions on solvent production in Clostridium acetobutylicum ATCC 824. Strain 824(pGROE1) was created to overexpress the groESL operon genes from a clostridial thiolase promoter. The growth of 824(pGROE1) was inhibited up to 85% less by a butanol challenge than that of the control strain, 824(pSOS95del). Overexpression of groESL resulted in increased final solvent titers 40% and 33% higher than those of the wild type and plasmid control strains, respectively. Active metabolism lasted two and one half times longer in 824(pGROE1) than in the wild type. Transcriptional analysis of 824(pGROE1) revealed increased expression of motility and chemotaxis genes and a decrease in the expression of the other major stress response genes. Decreased expression of the dnaKJ operon upon overexpression of groESL suggests that groESL functions as a modulator of the CIRCE regulon, which is shown here to include the hsp90 gene. Analysis of the plasmid control strain 824(pSOS95del) revealed complex host-plasmid interactions relative to the wild-type strain, resulting in prolonged biphasic growth and metabolism. Decreased expression of four DNA gyrases resulted in differential expression of many key primary metabolism genes. The ftsA and ftsZ genes were expressed at higher levels in 824(pSOS95del), revealing an altered cell division and sporulation pattern. Both transcriptional and Western analyses revealed elevated stress protein expression in the plasmid-carrying strain.

Metabolic phenotype of phosphoglucose isomerase mutants of Corynebacterium glutamicum

A series of experiments reported in the literature using fluxomics as an efficient functional genomics tool revealed that the l-lysine production of the Corynebacterium glutamicum strain MH20-22B correlates with the extent of intracellular NADPH supply. Some alternative metabolic engineering strategies to increase intracellular NADPH supply in the C. glutamicum strain DSM5715 were considered and finally the redirection of carbon flux through the pentose phosphate pathway with two NADPH generating enzymatic reactions was favored. Elsewhere, the construction of a phosphoglucose isomerase (Pgi) null mutant of the C. glutamicum strain DSM5715 has been described by utilizing genetic engineering as well as some aspects of its metabolic phenotype. Most interestingly, it was shown that not only could the l-lysine formation be increased by 1.7-fold but the by-product concentration for the null mutant strain was also able to be drastically reduced. In this publication we discuss this metabolic phenotype in detail and present additional data on by-product formation as well as yield considerations. Results from isotope based metabolic flux analysis in combination with considerations on NADPH metabolism clearly exclude the existence of Pgi isoenzymes in C. glutamicum strain DSM5715. The genome region containing the pgi gene was analyzed. It cannot be excluded that polar effects might have been caused by the disruption of the pgi gene and might have contributed to the observed metabolic phenotype of C. glutamicum Pgi mutants. We illustrate growth characteristics of a Pgi mutant of an industrial l-lysine production strain. A reduced growth rate and a biphasic growth behavior was observed. The importance of NADPH reoxidation for well balanced growth in Pgi mutants is discussed. Another phosphoglucose isomerase mutant of C. glutamicum has been described in literature with which an increase in l-lysine yield from 42 to 52% was observed. This finding highlights the general potential of metabolic flux redirection towards the pentose phosphate pathway, which could be used for metabolic engineering of the biotechnological synthesis of (1) aromatic amino acids and (2) chemicals whose synthesis depends on intracellular NADPH supply.

Growth of juvenile eels ( Anguilla spp.) in lowland streams in New Zealand

Growth rates of 2500 juvenile (<400 mm) shortfinned ( Anguilla australis) and longfinned eels ( A. dieffenbachii) in three lowland streams were estimated using burnt and stained otoliths. Growth rates averaged 17–27 mm per year in the first year of life but were then constant (9.4–19.8 mm per year) for the next 10 years. Rates were slow but comparable to those in similar forested and lowland streams elsewhere in New Zealand. Growth varied between individuals, waters and reaches. It was fastest (16.0 mm per year) in warm reaches (mean annual water temperatures >12.4 °C) with low eel densities (<14 g m 2). Growth was also positively correlated to the biomass of benthic macroinvertebrates. There were minor differences in growth between species and survey years. In the stream with the slowest growth rates, mature shortfinned males grew faster than immature eels. Parasite loads were low and considered unlikely to influence growth. It was concluded that, unless there is strong evidence of biphasic or asymptotic growth, simple linear growth equations, with a biologically realistic fixed intercept at age 0 or 1, should be used to describe the growth of juvenile and adult eels in New Zealand.

Shared control of maltose and trehalose utilization in Candida utilis.

Trehalose biosynthesis and its hydrolysis have been extensively studied in yeast, but few reports have addressed the catabolism of exogenously supplied trehalose. Here we report the catabolism of exogenous trehalose by Candida utilis. In contrast to the biphasic growth in glucose, the growth of C. utilis in a mineral medium with trehalose as the sole carbon and energy source is aerobic and exhibits the Kluyver effect. Trehalose is transported into the cell by an inducible trehalose transporter (K M of 8 mM and V MAX of 1.8 mol trehalose min-1 mg cell (dry weight)-1. The activity of the trehalose transporter is high in cells growing in media containing trehalose or maltose and very low or absent during the growth in glucose or glycerol. Similarly, total trehalase activity was increased from about 1.0 mU/mg protein in cells growing in glucose to 39.0 and 56.2 mU/mg protein in cells growing in maltose and trehalose, respectively. Acidic and neutral trehalase activities increased during the growth in trehalose, with neutral trehalase contributing to about 70% of the total activity. In addition to the increased activities of the trehalose transporter and trehalases, growth in trehalose promoted the increase in the activity of alpha-glucosidase and the maltose transporter. These results clearly indicate that maltose and trehalose promote the increase of the enzymatic activities necessary to their catabolism but are also able to stimulate each other's catabolism, as reported to occur in Escherichia coli. We show here for the first time that trehalose induces the catabolism of maltose in yeast.

Oil‐in‐Water Emulsion as a Model System to Study the Growth of Escherichia coli O157:H7 in a Heterogeneous Food System

ABSTRACT:Oil‐in‐water emulsions (hexadecane, minimal media [M9], and Tween 20) were used as model system to study the growth of Escherichia coli O157:H7. Stationary‐phase cell density decreased as the hexadecane concentration was increased (0%, 5%, 20%, and 40% [w/v]) and biphasic growth was observed in 40% emulsions supplemented with 0.4% glucose. Thin aggregate fimbriae (curli) were observed using SEM, and a greater percentage (Ps &lt;0.001) of curli‐producing colonies were isolated from 40% emulsions. Heat resistance (55 °C) of emulsion‐grown cells was greater than broth‐grown cells, indicating that growth and physiology under heterogeneous conditions differ from cells grown in liquid.

Biphasic kinetics of growth and bacteriocin production with Lactobacillus amylovorus DCE 471 occur under stress conditions.

Micro-organisms used during the production of fermented foods are subjected to several abiotic stresses. Microbial survival during these processes strongly depends on the ability of the cells to adapt and become more tolerant to the environmental conditions. Cultivation of Lactobacillus amylovorus DCE 471, a potential strain for use during type II sourdough fermentations, at low temperatures, unfavourable pH and high salt concentrations resulted in biphasic growth patterns. In addition, two separate bacteriocin peaks, as well as a dramatic change in cellular morphology, were observed. In general, an increase of the specific bacteriocin production occurred during the second growth phase. Finally, the observed sugar consumption profiles were affected by the applied fermentation temperature. Moreover, the highest bacteriocin activity occurred during maltose consumption at a low constant temperature of 28 degrees C and a constant pH of 5.4. Plate counts from both growth phases revealed the existence of two colony types. Irregular colonies were found to outnumber smoother colonies during the first growth phase, while the second growth phase was characterized by a greater number of smooth colonies. Electron microscopy was used to investigate the observed morphological switch at the single-cell level. Single, rod-shaped cells changed into elongated cells that grew in chains. Colony and cell morphology changes coincided with the biphasic growth pattern.

Prediction of critical cell growth behavior of Pseudomonas putida to maximize the cometabolism of 4-chlorophenol with phenol and sodium glutamate as carbon sources

In our study on cometabolism of 4-chlorophenol (4-cp) by Pseudomonas putida ATCC 49451 in the presence of phenol and a conventional carbon source, sodium glutamate (SG), a new biphasic cell growth pattern characterized by two exponential growth phases separated by an intermediate lag phase was observed. This biphasic growth pattern results from the toxicity disparity of 4-cp to phenol-degrading enzyme and SG-degrading enzyme activities. This paper presents further experimental study and model analysis to predict the occurrence of the biphasic growth pattern. Experimental results show that this growth pattern occurs at a high 4-cp concentration accompanied by a low phenol concentration and/or a high SG concentration. Using a set of growth kinetics equations developed earlier, which incorporates the cross-inhibition between the structurally dissimilar growth substrates (phenol and SG) and interactions between growth and non-growth substrates, as well as the toxicity of 4-cp, a criterion is proposed for predicting the occurrence of the biphasic growth pattern. These findings and model predictions not only help us to better understand the substrate interactions in the mixture and the toxicity of 4-cp, but they are also of practical significance in process control and design of a cometabolism system involving multiple substrates. For example, using the kinetics model, the ratio of phenol to 4-cp and the addition of SG to enhance cometabolism can be better defined to optimize the cometabolic treatment process.

Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation.

The Notch family of receptors and ligands plays an important role in cell fate determination, vasculogenesis, and organogenesis. Mutations of the Notch-3 receptor result in an arteriopathy that predisposes to early-onset stroke. However, the functional role of the Notch signaling pathway in adult vascular smooth muscle cells (VSMCs) is poorly characterized. This study documents that the Notch-3 receptor, the ligand Jagged-1, and the downstream transcription factor, HESR-1, are expressed in the normal adult rat carotid artery, and that this expression is modulated after vascular injury. In cultured VSMCs, both angiotensin II and platelet-derived growth factor (PDGF) markedly downregulated Notch-3 and Jagged-1 through ERK-dependent signaling mechanisms and prevented the glycosylation of Jagged-1. The downregulation of Jagged-1 and Notch-3 was associated with a decrease in CBF-1-mediated gene transcription activation and a fall in the mRNA levels of the downstream target transcription factor HESR-1. To test the hypothesis that the Notch pathway was coupled to growth regulation, we generated VSMC lines overexpressing the constitutively active form of Notch-3 (A7r5-N3IC). These cells exhibited a biphasic growth behavior in which the growth rate was retarded during the subconfluent phase and failed to decelerate at postconfluence. The lack of cell-cycle arrest in postconfluent A7r5-N3IC was associated with an attenuated upregulation of the cell-cycle inhibitor p27(kip) relative to control cells. This study documents the regulation of the Jagged-1 and Notch-3 genes in VSMCs by growth factor stimulation as well as a role for Notch-3 as a determinant of VSMC growth.