this study demonstrates that prolonged nicotine exposure increases the sympathetic neurotransmitter release in the foetal heart and causes programming of PKCε gene repression through promoter methylation, linking maternal smoking to pathophysiological consequences in the offspring heart.

The findings provide novel evidence of a causative role of increased DNA methylation in programming of heart hypertrophy and reduced cardiac contractility, and suggest potential therapeutic targets of demethylation in the treatment of failing heart and ischaemic heart disease.

]i was significantly greater for pressure-induced contraction of NPUA than that of PUA. Inhibition of PKC by calphostin C significantly attenuated the pressure-induced vascular tone and eliminated the difference of myogenic responses between NPUA and PUA. In contrast, the MAPKK (MEK) inhibitor PD-098059 had no effect on NPUA but significantly enhanced myogenic responses of PUA. In the presence of PD-098059, there was no difference in pressure-induced myogenic responses between NPUA and PUA. The results suggest that pregnancy downregulates pressure-dependent myogenic tone of the uterine artery, which is partly due to increased MEK/ERK activity and decreased PKC signal pathway leading to a decrease in Ca 2ϩ sensitivity of myogenic mechanism in the uterine artery during pregnancy.sheep; protein kinase C; extracellular signal-regulated kinase PREGNANCY IS ASSOCIATED WITH a significant increase in uterine blood flow that optimizes the delivery of oxygen and substrates to the developing fetus via the placenta. The adaptations in the uterine circulation to pregnancy are complex and are mediated in part by enhanced vasodilation and vascular remodeling. Previous studies (3,47,54,57) have focused on the endothelial adaptation and have shown an increase in endothelial nitric oxide synthesis/release in the uterine artery during pregnancy. The adaptation of smooth muscle contractile mechanisms is less clear. Pressure-dependent myogenic contraction is an important physiological mechanism that regulates basal vascular tone and is a significant contributor to the modulation of blood flow (6, 21). Myogenic response has been found as either increased or decreased in uterine arteries of pregnant, compared with nonpregnant, rats, mice, and rabbits (5, 42, 51).Although arterial myogenic behavior has been studied intensively for decades, the mechanisms by which vascular smooth muscle cells respond to changes in intraluminal pressure are still not fully understood. Previous studies (17,29,37) indicated that myogenic tone was highly dependent on an elevation of intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ). However, it has also been demonstrated that Ca 2ϩ sensitization mechanisms contribute to myogenic tone (28,30,49,50). Activation of various kinase cascades regulating Ca 2ϩ sensitivity of the contractile apparatus may modulate the level of arteriolar myogenic reactivity (8, 21). PKC has been proposed to play an important role in the regulation of basal vascular tone and arterial caliber, the major determinants of blood flow (6, 41, 44). Pressure-induced activation of PKC has been proposed to induce myogenic tone without additional increases in Ca 2ϩ concentrations or myosin light chain (MLC 20 ) phosphorylation (18, 31). Our recent studies have also demonstrated in ovine uterine arteries that activation of PKC causes sustained contractions in the absence of changes in [Ca 2ϩ ] i and MLC 20 phosphorylation levels (56) and that the PKC-mediated contraction is significantly attenuated in the uterine artery during pregnancy (...

Ca(2+) sparks are fundamental Ca(2+) signaling events arising from ryanodine receptor (RyR) activation, events that relate to contractile and dilatory events in the pulmonary vasculature. Recent studies demonstrate that long-term hypoxia (LTH) can affect pulmonary arterial reactivity in fetal, newborn, and adult animals. Because RyRs are important to pulmonary vascular reactivity and reactivity changes with ontogeny and LTH we tested the hypothesis that RyR-generated Ca(2+) signals are more active before birth and that LTH suppresses these responses. We examined these hypotheses by performing confocal imaging of myocytes in living arteries and by performing wire myography studies. Pulmonary arteries (PA) were isolated from fetal, newborn, or adult sheep that lived at low altitude or from those that were acclimatized to 3,801 m for > 100 days. Confocal imaging demonstrated preservation of the distance between the sarcoplasmic reticulum, nucleus, and plasma membrane in PA myocytes. Maturation increased global Ca(2+) waves and Ca(2+) spark activity, with sparks becoming larger, wider, and slower. LTH preferentially depressed Ca(2+) spark activity in immature pulmonary arterial myocytes, and these sparks were smaller, wider, and slower. LTH also suppressed caffeine-elicited contraction in fetal PA but augmented contraction in the newborn and adult. The influence of both ontogeny and LTH on RyR-dependent cell excitability shed new light on the therapeutic potential of these channels for the treatment of pulmonary vascular disease in newborns as well as adults.

Lung volume reduction surgery (LVRS) for emphysema has been suggested to improve patient lung function and activity. The short-term impact of LVRS on exercise performance was evaluated using maximal and submaximal steady-state exercise testing in 27 patients with severe hypoxemic chronic obstructive pulmonary disease (COPD), along with measurements of patient function, dyspnea, and quality of life. LVRS significantly improved exercise performance, due to ventilatory improvements associated with increased ventilatory reserve, enhanced tidal volume recruitment, and improved alveolar ventilation. Preoperative measurements of ventilatory reserve and dead space ventilation during exercise testing were closely associated with improved exercise performance. Improvements in patient dyspnea, walk distances, and quality of life also occurred following LVRS and were associated with improvements in exercise performance. Surgical mortality from LVRS was low (4%), but short-term all-cause mortality was increased (19%). Short-term mortality was associated with reduced expiratory muscle strength and markedly elevated dead space ventilation. We conclude that LVRS produces significant improvements in exercise performance, dyspnea, and quality of life in selected patients with COPD. Physiologic prediction of patients most likely to survive for an extended period and have significant benefit following LVRS may also be possible.