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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.
Am J Physiol Lung Cell Mol Physiol 2005 Aug
PMID:rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep. 1583 63

Evidence implies that nitric oxide (NO) in the central nervous systems mediates anorexia in tumor-bearing hosts. We have therefore evaluated, by immunohistochemical image analyses, net alterations of nitric oxide synthases (nNOS, eNOS, iNOS) in brain nuclei [paraventricular hypothalamic nucleus (PVN), medial habenular nucleus (MHB), lateral habenular nucleus (LHB), paraventricular thalamic nucleus (PV), lateral hypothalamic area (LHA), ventromedial hypothalamic nucleus (VMH), nucleus of the solitary tract (NTS)] of tumor-bearing mice (TB) with prostanoid-related anorexia. Pair-fed (PF) and freely fed (FF) non-tumor-bearing mice were used as controls. c-fos was analyzed as indicator of neuronal activation. nNOS was significantly increased in VMH and PVN from TB mice, while eNOS was significantly increased in LHB and LHA. iNOS was significantly increased in LHA and PVN nuclei, but decreased in MHB, LHB and VMH from tumor-bearers. However, several of these alterations were similarly observed in brain nuclei from pair-fed controls. Provision of unspecific NOS-antagonists to TB mice increased nNOS, eNOS and iNOS in several brain nuclei (PVN, LHA, VMH), but left tumor-induced anorexia unchanged. c-fos was significantly increased in all brain nuclei in PF mice except for NTS, LHA and PVN compared to controls, while tumor-bearing mice had increased c-fos in LHA and PVN only compared to controls. Our results demonstrate a complex picture of NOS expression in brain areas of relevance for appetite in tumor-bearing hosts, where most changes seemed to be secondary to stress during negative energy balance. By contrast, NOS content in PVN and LHA nuclei remains candidate behind anorexia in tumor disease. However, nitric oxide does not seem to be a primary mediator behind tumor-induced anorexia. NO may rather secondarily support energy intake in conditions with negative energy balance.
Brain Res Mol Brain Res 2005 Apr 04
PMID:NOS isoenzyme content in brain nuclei as related to food intake in experimental cancer cachexia. 1583 18

We previously reported a method for quantitative multi-gene transcriptional profiling with gene-specific standard curves using real-time PCR. Here, we report an approach that increases experimental throughput by using a master template to generate a single standard curve for the estimation of mRNA copy numbers from all genes. We prepared fifty-nine different templates and measured eNOS mRNA copy numbers in Matrigel VEGF-transfectant samples. The copy numbers obtained using each of the fifty-nine templates were within 50% of the copy number obtained using the previously reported method. Analysis of primer design parameters, and subsequent tests, showed that eliminating complementarities between the first nucleotides at the 5'-ends of the forward and reverse primers reduces the influence of saturation effects and produces copy numbers similar to those generated with gene-specific templates-generally, within 20%. Measurements on a panel consisting of eNOS, iNOS, and nNOS further validated the master-template approach. The master-template approach enables rapid quantification of mRNA abundances from panels of hundreds of genes, and will be a valuable tool for screening large numbers of genes as part of a search for biomarkers, the validation of DNA-microarray data, or research into the dynamics of the gene-protein network.
Exp Mol Pathol 2005 Aug
PMID:Quantitative multi-gene transcriptional profiling using real-time PCR with a master template. 1589 12

This study was performed to investigate the expression of the major isoforms of nitric oxide synthase mRNA and protein in the hypothalamo-pituitary-adrenal axis (HPA axis) of spontaneously hypertensive rats (SHR) at two different postnatal ages corresponding to the development of genetic hypertension. Using RT-PCR and Western blot techniques, the mRNA and protein levels of neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) isoforms were measured in 3- to 4-week-old (prehypertensive phase) and 12- to 13-week-old (established hypertension phase) SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. nNOS but not eNOS mRNA levels were increased at prehypertensive and hypertensive phases in SHR HPA axis. Compared to age-matched WKY rats, significantly higher levels of nNOS protein were found in the hypothalamus, lower levels in the adrenal glands and no changes were observed in the pituitary gland. At both ages tested, there was no significant change in eNOS protein expression in SHR HPA axis. The expression of iNOS mRNA and protein was under detection limit. In the HPA axis, the expression of nNOS isoform appears to be differentially controlled at the transcriptional and translational levels in SHR. Increased mRNA levels and differential nNOS protein expression from birth in SHR HPA axis may contribute in the pathogenesis of genetic hypertension.
Brain Res Mol Brain Res 2005 Aug 18
PMID:Expression of nitric oxide synthase isoforms in hypothalamo-pituitary-adrenal axis during the development of spontaneous hypertension in rats. 1591 38

Fish are known to express the three isoforms of nitric oxide synthase (NOS), the constitutive forms endothelial or eNOS, neuronal or nNOS and the inducible form iNOS. Most studies in fish have focussed on possible roles for NO in cardiovascular physiology although there has been recent attention on the role of nNOS in embryonic development. However compared to mammalian studies there have been relatively few studies on effects of nitric oxide (NO) on fish. Studies on heart and blood vessel preparations from various fish species appear to show results specific to the species or to the particular preparation. Possible roles of NO in the in vivo biology of adult fish or larval fish have received little attention. This article reviews effects of nitric oxide on cardiovascular physiology in fish with special emphasis on larval fish. It introduces some experimental work on possible signaling pathways in larval fish and introduces the possibility that NO could be an important environmental influence for some aquatic organisms. In higher vertebrates LPS (lipopolysaccharide) is known to activate the cytokine signaling system and stimulate increased expression of iNOS and increased production of NO, but this remains less investigated in fish. The effects of LPS on cardiovascular and osmoregulatory physiology of larval and juvenile salmonids are discussed and a possible role of NO in stress-induced drinking is suggested.
Comp Biochem Physiol A Mol Integr Physiol 2005 Oct
PMID:Role of nitric oxide in larval and juvenile fish. 1597 64

The mammalian heart expresses all three isoforms of nitric oxide synthases (NOS) in diverse cell types of the myocardium. Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart. They also attenuate the beta1-/beta2-adrenergic increase in inotropy and chronotropy, and reinforce the pre- and post-synaptic vagal control of cardiac contraction. By doing so, the NOS protect the heart against excessive stimulation by catecholamines, just as an "endogenous beta-blocker". In the ischemic and failing myocardium, induced iNOS further reinforces this effect, as does eNOS coupled to overexpressed beta3-adrenoceptors. nNOS expression also increases in the aging and infarcted heart, but its role (compensatory or deleterious) is less clear. In addition to their direct regulation of contractility, the NOS modulate oxygen consumption, substrate utilization, sensitivity to apoptosis, hypertrophy and regenerative potential, all of which illustrate the pleiotropic effects of this radical on the cardiac cell biology.
Comp Biochem Physiol A Mol Integr Physiol 2005 Oct
PMID:Regulation of the mammalian heart function by nitric oxide. 1598 81

Local adenoviral (Ad)-mediated gene transfer to the carotid artery of the stroke-prone spontaneously hypertensive rat (SHRSP) is successful in improving endothelial function. Here we explored the potential of systemic delivery of Ad encoding endothelial nitric oxide synthase (AdeNOS) to prevent elevation of blood pressure in the SHRSP using both nontargeted and vector targeting approaches. Systemic administration of nontargeted AdeNOS failed to modify the rise in blood pressure in SHRSP when administered during the 12th week of age (n = 5, P = 0.088, F = 3.0), an effect likely to result from sequestration of Ad by the liver. Rerouting Ad transduction using a bispecific antibody (anti-ACE/anti-Ad capsid, Fab9B9) that blocks Ad binding to the coxsackie and adenovirus receptor and simultaneously retargets AdeNOS to the angiotensin-converting enzyme resulted in efficient eNOS overexpression in the lung vasculature and a sustained hypotensive effect (n = 5, P = 0.007, F = 7.9). This study highlights the importance of vector targeting to achieve therapeutic gain and represents the first such study in cardiovascular gene therapy.
Mol Ther 2005 Aug
PMID:Targeting endothelial cells with adenovirus expressing nitric oxide synthase prevents elevation of blood pressure in stroke-prone spontaneously hypertensive rats. 1604

Loss of PKC-epsilon limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-epsilon would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC-epsilon wild-type (PKC-epsilon(+/+)), heterozygous null, and homozygous null (PKC-epsilon(-/-)) mice were exposed to normoxia or Hx for 5 wk. PKC-epsilon(-/-) mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-epsilon(+/+) mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-epsilon(+/+) mice) in both the proximal and distal PKC-epsilon(-/-) pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-epsilon(-/-) mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-epsilon(-/-) than PKC-epsilon(+/+) mice. In contrast, expression of nNOS in PKC-epsilon(+/+) mice decreased in response to chronic Hx, while lung levels in PKC-epsilon(-/-) mice remained unchanged. In summary, loss of PKC-epsilon results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC-epsilon appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.
Am J Physiol Lung Cell Mol Physiol 2005 Dec
PMID:Divergent contractile and structural responses of the murine PKC-epsilon null pulmonary circulation to chronic hypoxia. 1608 70

We previously reported association of eNOS with actin increases eNOS activity. In the present study, regulation of activity of eNOS by actin cytoskeleton during endothelial growth was studied. We found eNOS activity in PAEC increased when cells grew from preconfluence to confluence. eNOS activity was much greater in PAEC in higher density than those in lower density, suggesting increase in eNOS activity during cell growth is caused by increase in cell density. Although eNOS protein contents were also increased when endothelial cells grew from preconfluence to confluence, magnitude of increase in eNOS activity was much higher than increase in eNOS protein content, suggesting posttranslational mechanisms played an important role in regulation of eNOS activity during endothelial growth. Confocal fluorescence microscopy revealed eNOS was colocalized with G-actin in preconfluent cells in perinuclear region, with both G-actin in perinuclear area and cortical F-actin in plasma membrane in confluent cells. There was more beta-actin coimmunoprecipitated with eNOS in Triton X-100-soluble fraction in confluent cells in later growth phase and in high density. Decrease in eNOS association with beta-actin by silencing beta-actin expression using beta-actin siRNA causes inhibition of eNOS activity, NO production, and endothelial monolayer wound repair in PAEC. Moreover, PAEC incubation with cytochalasin D and jasplakinolide resulted in increases in eNOS/actin association and in eNOS activity without changes in eNOS protein content. Yeast two-hybrid experiments suggested strong association between eNOS oxygenase domain and beta-actin. These results indicate increase in eNOS association with actin is responsible for greater eNOS activity in confluent PAEC.
Am J Physiol Lung Cell Mol Physiol 2006 Jan
PMID:Growth and density-dependent regulation of NO synthase by the actin cytoskeleton in pulmonary artery endothelial cells. 1611 46

In mammals, much is understood about the endothelial and neural NO control mechanisms in the vasculature. In contrast, NO control of blood vessels in lower vertebrates is poorly understood, with the majority of research focusing on the presence of an endothelial NO system; however, its presence remains controversial. This study examined the mechanisms by which NO regulates the large blood vessels of non-mammalian vertebrates. In all species examined, the arteries and veins contained a plexus of NOS-positive perivascular nerves that included nerve bundles and fine, varicose nerve terminals. However, in the large arteries and veins of various species of fishes and amphibians, no anatomical evidence was found for endothelial NOS using both NADPH-diaphorase and eNOS immunohistochemistry. In contrast, perinuclear NOS staining was readily apparent in blue-tongue lizard, pigeon and rat, which suggested that eNOS first appeared in reptiles. Physiological analysis of NO signalling in the vascular smooth muscle of short-finned eel and cane toad could not find any evidence for endothelial NO signalling. In contrast, it appears that activation of the nitrergic vasomotor nerves is responsible for NO control of the blood vessels.
Comp Biochem Physiol A Mol Integr Physiol 2005 Oct
PMID:Nitric oxide control of lower vertebrate blood vessels by vasomotor nerves. 1613 37


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