The objective of this study was to determine if mechanisms involved in vascular dysfunction in type 2 diabetes differ with sex. Vascular reactivity, expression, and activation of rhoA and rho kinase were measured in aorta from male and female nondiabetic C57BLKS/J and diabetic BKS.Cg-m(+/+) Lepr(db)/J (db/db) mice, a model of type 2 diabetes. Relaxation to acetylcholine and nitroprusside was similar in aorta from nondiabetic male and female mice. Relaxation to acetylcholine was reduced approximately 50% in both male and female diabetic mice. Although inhibition of rho kinase with H-1152 increased relaxation to acetylcholine and nitroprusside in nondiabetic males, it had no effect on the response in either nondiabetic or diabetic females or diabetic males. Contraction to serotonin was increased similarly in male and female diabetic mice compared with nondiabetic mice and was reduced following inhibition of rho kinase with either fasudil or H-1152. Activation of rhoA and its downstream effector, rho kinase, was greater in aorta from diabetic males compared with nondiabetic males. In contrast, there were no differences in vascular activation of rhoA or rho kinase in diabetic females. The increased activity of rhoA and rho kinase in diabetic mice was not due to a change in protein expression of rhoA or rho kinase (ROCK1 and ROCK2) in vessels from either males or females. Although contractile dysfunction in vessels occurs in both male and female diabetic mice, the dysfunction in diabetic males is dependent upon activation of rhoA and rho kinase. Alternative mechanisms affecting rho kinase activation may be involved in females.

Object Three types of posterior thoracolumbar implants are in use today: pedicle screws, sublaminar titanium cables, and sublaminar hooks. The authors conducted a biomechanical comparison of these three implants in human cadaveric spines. Methods Spine specimens (T5–12) were harvested, radiographically assessed for fractures or metastases, and their bone mineral density (BMD) was measured. Individual vertebrae were disarticulated and fitted with either pedicle screws, sublaminar cables, or bilateral claw hooks. The longitudinal component of each construct consisted of bilateral 10-cm rods connected with two cross-connectors. The vertebral body was embedded in cement, and the rods were affixed to a ball-and-socket apparatus for the application of a distraction force. The authors analyzed 1) 20 vertebrae implanted with screws; 2) 20 with hooks, and 3) 20 with cables. The maximum pullout (MPO) forces prior to failure (mean ± standard deviation) for the screw, hook, and cable implants were 972 ± 330, 802 ± 356, and 654 ± 248 N, respectively (p = 0.0375). Cables allowed significantly greater displacement (6.80 ± 3.95 mm) prior to reaching the MPO force than hooks (3.73 ± 1.42 mm) and screws (4.42 ± 2.15 mm [p = 0.0108]). Eleven screw-implanted vertebrae failed because of screw pullout. All hook-and-cable—implanted vertebrae failed because of pedicle, middle column, or laminar fracture. Conclusions These findings suggest that screws possess the greatest pullout strength of the three fixation systems. Sublaminar cables are the least rigid of the three. When screw failure occurred, the mechanism was generally screw backout, without vertebral fractures.

Harrod JS, Rada CC, Pierce SL, England SK, Lamping KG. Altered contribution of RhoA/Rho kinase signaling in contractile activity of myometrium in leptin receptor-deficient mice. Am J Physiol Endocrinol Metab 301: E362-E369, 2011. First published May 10, 2011 doi:10.1152/ajpendo.00696.2010.-In late gestation, enhanced myometrial contractility is mediated in part through increased Rho/Rho kinase. Since leptin, which is elevated in pregnancy and obesity, can directly depress myometrial function, we hypothesized that in leptin receptor-deficient mice, myometrial contractility would be greater in late pregnancy due to increased Rho/Rho kinase activity. To test this, we correlated RhoA and Rho kinase expression to contractility in myometrium from nonpregnant (NP) and late-pregnant (P18) heterozygous leptin receptor-deficient mice (db/ϩ) vs. wild-type (WT) mice. In NP mice, KCl-induced contractions were similar between WT and db/ϩ myometrium. However, the Rho kinase-dependent component of the contractions was greater in db/ϩ mice, along with an increased expression of Rho kinase. KCl-induced contractions increased in strength in myometrium from P18 WT and db/ϩ compared with NP. Although the contribution of Rho kinase to contractions was unchanged in P18 WT mice, it was decreased in P18 db/ϩ mice. The decrease in Rho kinase-dependent contractions in P18 db/ϩ mice coincided with reduced RhoA and Rho kinase expression relative to NP db/ϩ. Addition of high-fat-induced abnormal glucose utilization prevented changes in Rho kinase function. We conclude that abnormal leptin signaling increases expression and function of Rho kinase to maintain contractile function in NP myometrium and that during pregnancy the contribution of RhoA and Rho kinase expression to myometrial function is reduced despite an increase in myometrial contractility. Thus, other signaling mechanisms appear to compensate when leptin signaling is reduced to maintain contractile function during pregnancy. pregnancy; obesity; gestational diabetes CURRENTLY IN THE US, one in five pregnant women is obese, which is associated with increased perinatal mortality and morbidity and a fivefold increase in the average cost of prenatal care and hospital stay (12,20,28). Maternal complications in both overweight and obese women include development of gestational diabetes (GDM), preeclampsia, increased miscarriages and preterm births, poor labor progression, and failed spontaneous term deliveries (15,28,44). Because of the failure to deliver spontaneously in obese mothers, the number of postterm labor inductions and cesarean deliveries is high. The increased number of cesarean sections cannot be explained by an increased infant birth weight (44). These pregnancy-associated complications observed in obese women suggest that maternal obesity has a significant impact on myometrium, which is due possibly to abnormal uterine smooth muscle function. This notion is supported by the finding that both the force and frequency of spontaneous contractions are markedly decreased in my...

Although 5HT2A receptors mediate contractions of normal arteries to serotonin (5HT), in some cardiovascular diseases, other receptor subtypes contribute to the marked increase in serotonin contractions. We hypothesized that enhanced contractions of arteries from diabetics to 5HT are mediated by an increased contribution from multiple 5HT receptor subtypes. We compared responses to selective 5HT receptor agonists and expression of 5HT receptor isoforms (5HT1B, 5HT2A, and 5HT2B) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7 m+/+Leprdb/J). 5HT, 5HT2A (TCB2 and BRL54443), and 5HT2B (norfenfluramine and BW723C86) receptor agonists produced concentration-dependent contractions of ND arteries that were markedly increased in DB arteries. Neither ND nor DB arteries contracted to a 5HT1B receptor agonist. MDL11939, a 5HT2A receptor antagonist, and LY272015, a 5HT2B receptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of 5HT1B, 5HT2A, and 5HT2B receptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and 5HT2A and 5HT2B receptor agonists in ND and DB. We conclude that in contrast to other cardiovascular diseases, enhanced contraction of arteries from diabetics to 5HT is not due to a change in expression of multiple 5HT receptor subtypes.

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