The proliferation, differentiation, and protein synthesis of vascular smooth muscle cells (SMCs) play important roles in vascular remodeling. Here, we compared the genetic programming and signaling of SMCs in collagen matrix as a three-dimensional (3-D) environment and on a two-dimensional (2-D) surface. By using DNA microarrays with 9600 genes, we showed that 77 genes were expressed more than twofold and 22 genes were less than one-half in 3-D matrix, when compared with the 2-D condition. The higher expression level of cyclin-dependent kinase inhibitor 1 (p21) in 3-D matrix suggests that p21 may be responsible for the lower proliferation rate in 3-D matrix. The expression level of collagen I was higher in 3-D matrix, suggesting that SMCs in 3-D matrix have increased matrix synthesis. In addition, SMCs in 3-D matrix had less stress fibers and focal adhesions, and a lower level of tyrosine phosphorylation of focal adhesion kinase (FAK). Overexpression of FAK attenuated the expression of p21 and collagen I in 3-D matrix, suggesting that FAK functions as a molecular switch for cell cycle regulation and matrix synthesis. The information generated in this study helps to elucidate the molecular basis of the modulation of SMC phenotypes by the extracellular matrix.

ABSTRACT:In vivo studies have demonstrated that prenatal or neonatal exposure to polybrominated diphenyl ethers (PBDEs) causes developmental neurotoxicity. However, there is a lack of human data. Our hypothesis was that PBDEs would result in lower infant neurodevelopment scores. This is a post hoc analysis of previous studies. Fourteen PBDEs in 70 breast milk were analyzed using a high-resolution gas chromatograph/high-resolution mass spectrometer. Infant neurodevelopment at the age of 8 -12 mo was determined using the Bayley Scales of Infants and Toddlers Development, third edition (Bayley-III). The median of ⌺ 14 PBDEs (the sum of 14 PBDE congeners) was 2.92 ng/g lipid. The ⌺ 14 PBDE concentrations were not correlated with Bayley-III scores on cognitive, language, motor, social-emotional, or adaptive behavior scales. A significantly inverse association between brominated diphenyl ether (BDE)-209 and the cognitive scale was found after multivariate stepwise linear regression analyses (B ϭ Ϫ0.007, adjusted R ϭ Ϫ0.224, p ϭ 0.032). In contrast, the language scale was positively correlated with BDE-196 (B ϭ 0.096, adjusted R ϭ 0.315, p ϭ 0.002). Our results are consistent with most in vivo studies, suggesting that prenatal or postnatal exposure to BDE-209 potentially delays the neurological development. (Pediatr Res 70: 596-600, 2011) P olybrominated diphenyl ethers (PBDEs), which are only used as brominated flame retardants, are widely found in a variety of commercial and household products including foam furniture padding, plastics, electrical equipment, paints, textiles, construction materials, and vehicles (1). PBDEs are similar in structure to polychlorinated biphenyls; but in contrast to point sources of polychlorinated biphenyl contamination, PBDEs are widespread and released into the environment from more sources (2).A marked period of rapid brain growth and development begins in humans during the third trimester of pregnancy and continues throughout the first 2 y of life. PBDE congeners are considered to be neurotoxicants, although more work needs to be done to determine whether in utero and postnatal exposure to PBDEs has any adverse effects on human neurodevelopment, and the effects of PBDEs on human health remain unclear (3). However, recent studies have shown that human exposure to PBDEs causes a reduction in women's fecundability (4), a prolongation of menstruation periods (5), an increase in serum LH in male infants (6), and disruption of thyroxine (T4), triiodothyronine (T3) and thyroid-stimulating hormones in male adults (7), and a positive association with diabetes prevalence (8).Postnatal infant exposure to PBDEs mainly comes from breast milk and house dust (9); moreover, PBDE levels in infants and children are higher than those in adults (10). Recently, epidemiological studies of in utero exposure to PBDEs have found it to be associated with the physiological and neurological development of infants and children (6,(11)(12)(13)(14)(15)(16). In addition, lower birth weights were correlated with hi...

The aim of this study was to identify the health hazards and possible exposure surveillance markers of workers exposed to nanoparticles during manufacturing and application in comparison to a group of unexposed workers. For this longitudinal study, we recruited 158 nanomaterial-handling workers and 104 non-exposed workers from 14 manufacturing plants in Taiwan (baseline). Among them, 124 nanomaterial-handling workers and 77 unexposed workers were monitored 6 months later. We investigated pulmonary and cardiovascular disease markers, inflammation and oxidative stress markers, antioxidant enzymes and genotoxicity markers. Antioxidant enzymes (superoxide dismutase, glutathione peroxidase) and cardiovascular markers (vascular cell adhesion molecule, paraoxonase) were significantly associated with nanomaterial-handling during the 6-month follow-up period. In addition, the small airway damage marker (Clara cell protein 16) and lung function test parameters were also significantly associated with handling nanomaterials. The study markers and lung function tests are possible markers that could be useful for surveillance of nanomaterial-handling workers.

Vascular endothelium transduces the temporal gradients in shear stress (tau) originating from unsteady blood flow into functional responses. We measured the effects of step-tau and ramp-tau (i.e., t with different temporal shear gradients) on the lipid lateral diffusion coefficient (D) in the apical membranes of confluent cultured bovine aortic endothelial cells by using fluorescence recovery after photobleaching. A step-tau of 10 dynes/cm2 elicited a rapid (5 s) increase of D in the portion of the cell upstream of the nucleus and a concomitant decrease in the downstream portion. A ramp-tau with a rate of 20 dynes/cm2 per min elicited a rapid (5 s) decrease of D in both the upstream and the downstream portions. The mitogen-activated protein kinases (MAPKs) ERK and JNK were activated by step-tau but not by ramping to the same tau level. Benzyl alcohol, which increases D, enhanced the activities of both MAPKs; cholesterol, which reduces D, diminished these activities. We conclude that the lipid bilayer can sense the temporal features of the applied tau with spatial discrimination and that the tau-induced membrane perturbations can be transduced into MAPK activation. These results have implications for understanding the role of t in modulating vascular functions in health and disease.

Endothelial cell (EC) migration is required for vascular development and wound healing. We investigated the roles of microtubule (MT) dynamics and the small GTPase Rac in the fluid shear stress-induced protrusion of lamellipodia and enhancement of migration of bovine aortic ECs (BAECs). Shear stress increased lamellipodial protrusion and cell migration. Treating BAECs with paclitaxel (Taxol), an MT-stabilizing agent, inhibited lamellipodial protrusion and reduced migration speed in both the static and sheared groups. After Taxol washout, both lamellipodial protrusion and cell migration increased in the flow direction. Taxol treatment also decreased the shear-induced Rac activation. Transfection of BAECs with a dominant negative mutant of Rac1 inhibited lamellipodial protrusion and cell migration under static and shear conditions. Transfection with an activated mutant of Rac1 induced lamellipodia in all directions and attenuated the shear-induced migration, suggesting that an appropriate level of Rac activity and a polarized lamellipodial protrusion are important for cell migration under static and shear conditions. Our findings suggest that MT dynamics and optimum Rac activation are required for the polarized protrusion of lamellipodia that drives the directional EC migration under flow.

We studied the response of porcine vascular smooth muscle cells (PVSMCs) to cyclic sinusoidal stretch at a frequency of 1 Hz. Cyclic stretch with an area change of 25% caused an increase in PVSMC apoptosis, which was accompanied by sustained activation of c-Jun NH(2)-terminal kinases (JNK) and the mitogen-activated protein kinase p38. Cyclic stretch with an area change of 7% had no such effect. Infection of PVSMCs with recombinant adenoviruses expressing constitutively active forms of upstream molecules that activate JNK and p38 also led to apoptosis. The simultaneous blockade of both JNK and p38 pathways with adenovirus-mediated expression of dominant-negative mutants of c-Jun and p38 caused a significant decrease (to 1/2) of the apoptosis induced by 25% cyclic stretch. The 25% stretch also caused sustained clustering of tumor necrosis factor-alpha (TNF-alpha) receptor-1 and its association with TNF-alpha receptor-associated factor-2 (TRAF-2). Overexpressing the wild-type TRAF-2 in PVSMCs caused an increase in apoptosis. In contrast, the expression of a dominant-negative mutant of TRAF-2 attenuated stretch-induced apoptois. These results support the hypothesis that circumferential overload under hypertensive conditions induces a clustering of death receptors that cause vascular smooth muscle cell apoptosis.

The study aimed to examine the impact of prenatal exposure to polybrominated diphenyl ethers (PBDEs) on infant neurodevelopment. PBDEs levels in 36 cord blood samples were analyzed with a high-resolution-gas-chromatograph/high-resolution-mass-spectrometer and infant neurodevelopment was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. The mean and median of Σ(11)PBDEs were 6.63 and 4.63 ng/g lipid, respectively. As compared to the lower PBDEs group (Σ(11)PBDEs < 4.63 ng/g lipid), the higher PBDEs group (Σ(11)PBDEs > 4.63 ng/g lipid) had a significantly higher actual odds ratio (OR = 1.13, p < 0.05) of the cognition score as well as a lower odds ratio (OR = 0.904, p < 0.01) of the adaptive behavior score, suggesting that prenatal PBDEs exposure may potentially affect infant neurodevelopment.

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