Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long-term antihypertensive effects.

NO deficiency is associated with development of hypertension. Defects in the renal citrulline-arginine pathway or arginine reabsorption potentially reduce renal NO in prehypertensive spontaneously hypertensive rats (SHRs). Hence, we investigated genes related to the citrulline-arginine pathway or arginine reabsorption, amino acid pools, and renal NO in 2-week-old prehypertensive SHRs. In addition, because perinatally supporting NO availability reduces blood pressure in SHRs, we supplemented SHR dams during pregnancy and lactation with citrulline, the rate-limiting amino acid for arginine synthesis. In female offspring, gene expression of argininosuccinate synthase (involved in renal arginine synthesis) and renal cationic amino acid Y-transporter (involved in arginine reabsorption) were both decreased in 2-day and 2-week SHRs compared with normotensive WKY, although no abnormalities in amino acid pools were observed. In addition, 2-week-old female SHRs had much less NO in their kidneys (0.46+/-0.01 versus 0.68+/-0.05 nmol/g of kidney weight, respectively; P<0.001) but not in their heart. Furthermore, perinatal supplementation with citrulline increased renal NO to 0.59+/-0.02 nmol/g of kidney weight (P<0.001) at 2 weeks and persistently ameliorated the development of hypertension in females and until 20 weeks in male SHR offspring. Defects in both the renal citrulline-arginine pathway and in arginine reabsorption precede hypertension in SHRs. We propose that the reduced cationic amino acid transporter disables the developing SHR kidney to use arginine reabsorption to compensate for reduced arginine synthesis, resulting in organ-specific NO deficiency. This early renal deficiency and its adverse sequels can be corrected by perinatal citrulline supplementation persistently in female and transiently in male SHRs.

Chronic kidney disease after myeloablative allogeneic hematopoietic stem cell transplantation.

Because survival of recipients of allogeneic hematopoietic stem cell transplantation (HSCT) has improved, long-term complications become more important. We studied the incidence and risk factors of chronic kidney disease in these patients and evaluated associated posttransplant complications and mortality. We performed a retrospective cohort study of 266 adults who received myeloablative allogeneic HSCT and who survived for >6 months in an 11-year period at a Dutch university medical center. Primary outcome was the incidence of chronic kidney disease defined as a glomerular filtration rate (GFR) of <60 mL/min/1.73 m(2). Chronic kidney disease developed in 61 (23%) of 266 patients, with a cumulative incidence rate of 27% at 10 years. Severe kidney disease (GFR of <30 mL/min/1.73 m(2)) developed in 3% of patients. Only 6 patients developed the thrombotic microangiopathic syndrome SCT nephropathy, and 2 of them needed dialysis. Pretransplant risk factors for chronic kidney disease were lower GFR at day 0 (P < .0001, odds ratio [OR] 0.95 95% confidence interval [CI] 0.93-0.97), female gender, and higher age (P = .001 and P < .0001, respectively). The occurrence of hypertension after transplantation was associated with chronic kidney disease (P < .0001, OR 0.34 95% CI 0.18-0.62). Mortality was 39% after a mean follow-up of 5.1 years. There was no significant difference in survival between patients with and without chronic kidney disease. Chronic kidney disease is a common late complication of myeloablative allogeneic HSCT. Because of the natural decline in renal function with time there is a risk of developing end-stage renal disease in the future. SCT nephropathy seems to be a specific cause of chronic kidney disease that is typically associated with severe kidney disease.

Met-RANTES reduces endothelial progenitor cell homing to activated (glomerular) endothelium in vitro and in vivo.

The chemokine RANTES (regulated upon activation normal T-cell expressed and secreted) is involved in the formation of an inflammatory infiltrate during glomerulonephritis. However, RANTES receptor inhibition, although reducing glomerular leukocyte infiltration, can also increase damage. We hypothesized that RANTES does not only promote the influx and activation of inflammatory leukocytes but also mediates glomerular microvascular repair by stimulating the homing of bone marrow (BM)-derived endothelial progenitor cells. To investigate the role of RANTES in the participation of BM-derived cells in glomerular vascular repair, we used a rat BM transplantation model in combination with reversible anti-Thy-1.1 glomerulonephritis. Twenty-four hours after the induction of glomerulonephritis, BM-transplanted rats were treated for 7 days with either the RANTES receptor antagonist Met-RANTES or saline. The participation of BM-derived endothelial cells in glomerular repair, glomerular monocyte infiltration, and proteinuria was evaluated at days 7 and 28. Furthermore, we used an in vitro perfusion chamber assay to study the role of RANTES receptors in shear-resistant adhesion of the CD34+ stem cells to activated endothelium under flow. In our reversible glomerulonephritis model, RANTES receptor inhibition specifically reduced the participation of BM-derived cells in glomerular vascular repair by more than 40% at day 7 without impairing monocyte influx. However, no obvious change in recovery from proteinuria or morphological damage was observed. Blockade of RANTES receptors on CD34+ cells in vitro partially inhibited platelet-enhanced, shear-resistant firm adhesion of the CD34+ cells to activated endothelium. In conclusion, our data suggest that RANTES is involved in the homing and participation of BM-derived endothelial cells in glomerular repair.

Sympathetic hyperactivity in haemodialysis patients is reduced by short daily haemodialysis.

OBJECTIVE: Haemodialysis patients often have sympathetic hyperactivity. The hypothesis of this study was that a switch from three times weekly to short daily dialysis could affect sympathetic hyperactivity. METHODS: We studied 11 patients (eight men; aged 46 +/- 8 years) stable on haemodialysis for at least 1 year before and 6 months after conversion from three times to six times weekly dialysis without increasing total dialysis time (short daily dialysis). Seven patients were restudied 2 months after switching back to three times weekly haemodialysis. RESULTS: Ultrafiltration volume per session decreased from 2.4 +/- 1.0 to 1.5 +/- 0.6 l (P < 0.05). The extracellular fluid volume (bromide distribution space) did not change. Mean arterial pressure (without medication) decreased from 113 +/- 11 to 98 +/- 9 mmHg (P < 0.05). Cardiac output (Doppler echocardiography) did not change, but peripheral vascular resistance decreased from 25.4 +/- 6.4 to 21.2 +/- 3.2 mmHg per min/l (P < 0.05), in conjunction with a decrease in muscle sympathetic nerve activity (MSNA) from 39 +/- 19 to 28 +/- 15 bursts/min (P < 0.05). Ambulant 24 h blood pressure decreased and the nocturnal blood pressure dip increased during short daily dialysis. The seven patients who were switched back to alternate day haemodialysis showed a return of the high MSNA and peripheral vascular resistance. CONCLUSION: The study shows that sympathetic hyperactivity in haemodialysis patients is reduced by increasing the frequency of treatment sessions. This is probably because of the decrease in number or magnitude of the fluid fluctuations.

Haematopoietic and endothelial progenitor cells are deficient in quiescent systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with a high prevalence of cardiovascular disease. Circulating endothelial progenitor cells (EPCs) contribute to vascular regeneration and repair, thereby protecting against atherosclerotic disease. EPCs are derived from CD34+ haematopoietic stem cells (HSCs), which have an increased propensity for apoptosis in the bone marrow of patients with SLE. AIM: To determine whether circulating HSCs and EPCs are reduced in SLE, contributing to an increased cardiovascular risk. METHODS: Progenitor cells were sampled from 15 female patients with SLE in prolonged clinical remission from their disease and 15 matched healthy controls. HSC and CD34+KDR+ EPCs were quantified by flow cytometry. Annexin V staining was used to identify apoptotic cells. RESULTS: Patients with SLE had reduced levels of circulating CD34+ HSCs and CD34+KDR+ EPCs, associated with increased HSC apoptosis. Compared with controls, the fraction of HSCs that could be identified as EPCs was higher in patients with SLE, consistent with a primary defect of HSCs. EPC outgrowth from mononuclear cells, which depends mainly on CD34- cells, was unaffected. CONCLUSIONS: Patients with SLE have lower levels of circulating HSCs and EPCs, even during clinical remission. The data suggest that increased HSC apoptosis is the underlying cause for this depletion. These observations indicate that progenitor cell-mediated endogenous vascular repair is impaired in SLE, which may contribute to the accelerated development of atherosclerosis.

End-stage renal disease causes an imbalance between endothelial and smooth muscle progenitor cells.

Patients with end-stage renal disease (ESRD) on hemodialysis have an increased risk of cardiovascular disease (CVD). Circulating endothelial progenitor cells (EPC) contribute to vascular regeneration and repair, thereby protecting against CVD. However, circulating smooth muscle progenitor cells (SPC) may contribute to adverse vascular remodeling. We hypothesized that an imbalance occurs between EPC and SPC in ESRD patients and sampled progenitor cells from 45 ESRD patients receiving regular treatment. Our study is the first to show reduced numbers of CD34+KDR+ hematopoietic stem cell (HSC)-derived EPC (type I EPC). Furthermore, monocyte-derived EPC cultured from mononuclear cells (type II EPC) were reduced in number and had a reduced capacity to stimulate endothelial cell angiogenesis. In contrast, SPC outgrowth was unaffected. In vitro incubation with uremic serum impaired type II EPC outgrowth from healthy donor mononuclear cells and did not influence SPC outgrowth. The hemodialysis procedure itself induced HSC apoptosis and caused an acute depletion of circulating EPC. Taken together, the decreased number and impaired function of EPC are compatible with impaired endogenous vascular repair in hemodialysis patients, whereas the unaffected SPC numbers suggest that the potential of progenitor cells to contribute to adverse remodeling is retained. This EPC-SPC imbalance may contribute to the acceleration of CVD in ESRD patients and could offer novel therapeutic targets.

Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment.

Standard treatment in chronic kidney disease (CKD) patients includes an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. CKD is often characterized by sympathetic hyperactivity. This study investigates the prevalence of sympathetic hyperactivity (quantified by assessment of muscle sympathetic nerve activity [MSNA]) in a sizable group of patients with CKD and assessed whether chronic angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker normalizes increased MSNA. In 74 CKD patients (creatinine clearance 54+/-31 mL/min), MSNA, blood pressure, and plasma renin activity were measured in the absence of antihypertensive drugs except for diuretics. In a subgroup of 31 patients, another set of measurements was obtained after > or =6 weeks of enalapril (10 mg PO), losartan (100 mg PO), or eprosartan (600 mg PO). Patients as compared with control subjects (n=82) had higher mean arterial pressure (113+/-13 versus 89+/-7 mm Hg), MSNA (31+/-13 versus 19+/-7 bursts per minute), and log plasma renin activity (2.67+/-036 versus 2.40+/-0.32 fmol/L per second; all P<0.001). During angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy (n=31), mean arterial pressure (115+/-11 to 100+/-9 mm Hg) and MSNA (33+/-11 to 25+/-9 bursts per minute) decreased (both P<0.01) but were still higher than in control subjects (both P<0.01). Multiple regression analysis identified age and plasma renin activity as predictive for MSNA. In conclusion, sympathetic hyperactivity occurs in a substantial proportion of hypertensive CKD patients. Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment reduces but does not normalize MSNA.

Transcriptome-based identification of pro- and antioxidative gene expression in kidney cortex of nitric oxide-depleted rats.

Nitric oxide (NO) depletion in rats induces severe endothelial dysfunction within 4 days. Subsequently, hypertension and renal injury develop, which are ameliorated by alpha-tocopherol (VitE) cotreatment. The hypothesis of the present study was that NO synthase (NOS) inhibition induces a renal cortical antioxidative transcriptional response and invokes pro-oxidative and proinflammatory gene expression due to elimination of dampening effects of NO and enhanced oxidative stress. Male Sprague-Dawley rats received NOS inhibitor N(omega)-nitro-l-arginine (l-NNA, 500 mg/l water) for 4 (4d-LNNA), 21 (21d-LNNA), or 21 days with VitE in chow (0.7 g/kg body wt/day). Renal cortical RNA was applied to oligonucleotide rat arrays. In 4d-LNNA, 21d-LNNA, and 21d-LNNA+VitE, 120, 320, and 184 genes were differentially expressed, respectively. Genes related to glutathione and bilirubin synthesis were suppressed during 4d and 21d-LNNA and not corrected by VitE. Proteinuria, tubulointerstitial macrophages, and heme-oxygenase-1 (HO-1) expression were strongly correlated. Remarkably, pro-oxidative genes were not induced. Inflammation- and injury-related genes, including kidney injury molecule-1 and osteopontin, were unchanged at day 4, induced at 21d, and partly corrected by VitE. Superimposing HO-1 inhibition on NOS inhibition had no impact on the development of hypertension. To summarize, renal expression of genes involved in synthesis of the antioxidants glutathione and bilirubin seemed directly NO dependent, but there were no direct effects of NO depletion on pro-oxidant systems. This indicates that renal transcriptional regulation of two defense systems, glutathione and bilirubin syntheses, seems to depend upon adequate NO synthesis. Interaction between NO synthesis and heme degradation pathways for blood pressure regulation was not found.

Low albumin levels increase endothelial NO production and decrease vascular NO sensitivity.

BACKGROUND: Hypoalbuminaemia is associated with increased risk of cardiovascular disease. It is unclear whether endothelial dysfunction is a direct result of low albumin or whether it is caused by factors like chronic inflammation or dyslipidaemia. In this study, the effect of low albumin concentrations on endothelial nitric oxide synthase (eNOS)-dependent NO production was determined in vitro and ex vivo. METHODS: eNOS activity, assessed by arginine-citrulline conversion, and NO production, determined by 4,5-diaminofluorescein diacetate, electron paramagnetic resonance and Griess colorimetry, were measured in cultured endothelial cells expressing high levels of eNOS (bEnd.3) after exposure to albumin concentrations ranging from 0.5 mmol/l (33 g/l) to 0 mmol/l. Analbuminaemic and control rat plasma NO metabolites and aortic eNOS protein mass were determined, and aortic endothelium-independent and endothelium-dependent vasodilator tone were measured ex vivo under albumin-free conditions. RESULTS: In vitro, eNOS activity was significantly increased in the absence of albumin (75 +/- 2 vs 26 +/- 6 pmol/min/mg protein; P < 0.01). Low albumin levels consistently increased NO production in endothelial cells. Plasma NO metabolites were increased (18.2 +/- 1.9 vs 12.5 +/- 0.8 micromol/l; P < 0.05) and endothelium-independent relaxation was markedly blunted in analbuminaemic rats, resulting in a considerably higher ED50 (80 +/- 2 vs 1.1 +/- 0.2 nmol/l, P < 0.01), while endothelium-dependent dilatation was slightly, but significantly, increased. Aortic eNOS protein mass was not affected. This implies that in vivo hypoalbuminaemia reduces vascular NO sensitivity. CONCLUSION: We show that low albumin as such seems to enhance, rather than diminish, eNOS-mediated endothelial NO production.

Water immersion in preeclampsia.

OBJECTIVE: Preeclampsia is associated with profound vasoconstriction in most organ systems and reduced plasma volume. Because water immersion produces a marked central redistribution of blood volume and suppresses the renin-angiotensin system response and sympathetic activity, we hypothesized that water immersion might be useful in the treatment of preeclampsia. STUDY DESIGN: The effects of thermoneutral water immersion for 3 hours on central and peripheral hemodynamics were evaluated in 7 preeclamptic patients, 7 normal pregnant control patients, and 7 nonpregnant women. Finger plethysmography was used to determine hemodynamic measurements (cardiac output and total peripheral resistance), and forearm blood flow was measured by strain gauge plethysmography. Postischemic hyperemia was used to determine endothelium-dependent vasodilation. Analysis was by analysis of variance for repeated measurements. RESULTS: During water immersion cardiac output increased while diastolic blood pressure and heart rate decreased, although systolic blood pressure remained unchanged in each group. Forearm blood flow increased significantly in the normal pregnant and preeclamptic subjects. Total peripheral resistance decreased in all groups, but values in preeclamptic patients remained above those of normotensive pregnant women. Water immersion had no effect on endothelium-dependent vasodilation in the preeclamptic group, and most hemodynamic changes that were observed reversed to baseline within 2 hours of completion of the procedure. CONCLUSION: Although water immersion results in hemodynamic alterations in a manner that is theoretically therapeutic for women with preeclampsia, the effect was limited and short-lived. In addition water immersion had no effect on endothelium-dependent vasodilation in women with preeclampsia. The therapeutic potential for water immersion in preeclampsia appears to be limited.

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors.

We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.

Anti-oxidant sensitivity of donor age-related gene expression in cultured fibroblasts.

Cultured human fibroblasts display age-dependent transcriptomic differences. We hypothesized that aging-associated oxidative stress affects gene expression, and monitored the transcriptome in confluent fibroblasts from young and old individuals cultured without and with a lipophilic and hydrophilic anti-oxidant mixture (vitamin E, quercetin, hydroxytyrosol and kaempferol). In cells derived from old subjects genes with lower expression were related to oxidative stress, growth and differentiation, cell cycle or metabolic enzymes and with higher expression to protein processing and docking, extracellular matrix, immune response, EGF-signalling and transcription. Anti-oxidant treatment modulated a similar number of genes in all donors and induced cell cycle regulatory genes. A subset of genes, modulated by age and inversely modulated by anti-oxidants, included glutaminase. Despite increased glutaminase expression, donor age-dependent decline in glutathione content and resistance to glutathione-depletion was observed. Summarizing, gene expression of fibroblasts is affected by donor age and a subset was corrected by anti-oxidants. Thus, in cultured fibroblasts from aged donors, gene expression is partly driven by oxidative stress.

Role of circulating karyocytes in the initiation and progression of atherosclerosis.

Cardiovascular disease is still hard to predict in an individual. The main focus in cardiovascular research has been on endothelial cells and vascular smooth muscle cells of the vessel wall and their interactions with the blood flow. Alterations in the properties of the blood have received a lot of attention in biochemical terms. Interestingly, alterations in the properties of circulating cells have received less attention. We propose that presence of 1 or more risk factors together with normal physiological stimuli induce redox-dependent changes in leukocyte gene transcription with pathophysiological responses. Thus, risk factors render leukocytes hypersensitive to normal stimuli. Risk factors can be subdivided into physical and chemical factors. Superimposed on physiological regulators of leukocyte function, these risk factors promote a cellular pro-oxidative state. Redox-sensitive transcription factors are activated, leading to responses involving inflammation, adhesion, migration, and additional reactive oxygen species generation. As a consequence, monitoring of individual gene expression signatures of these cells could well increase our understanding of the mechanisms by which leukocytes and, in particular, monocytes function. Furthermore, transcriptomes of these cells could be used to investigate the aggressiveness of the atherosclerotic process or to guide treatment in the patient with risk factors for atherosclerosis.

Tetrahydrobiopterin, but not L-arginine, decreases NO synthase uncoupling in cells expressing high levels of endothelial NO synthase.

Endothelial NO synthase (eNOS) produces superoxide when depleted of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) and L-arginine by uncoupling the electron flow from NO production. High expression of eNOS has been reported to have beneficial effects in atherosclerotic arteries after relatively short periods of time. However, sustained high expression of eNOS may have disadvantageous vascular effects because of uncoupling. We investigated NO and reactive oxygen species (ROS) production in a microvascular endothelial cell line (bEnd.3) with sustained high eNOS expression and absent inducible NOS and neuronal NOS expression using 4,5-diaminofluorescein diacetate and diacetyldichlorofluorescein as probes, respectively. Unstimulated cells produced both NO and ROS. After stimulation with vascular endothelial growth factor (VEGF), NO and ROS production increased. VEGF-induced ROS production was even further increased by the addition of extra L-arginine. Nomega-nitro-L-arginine methyl ester decreased ROS production. These findings strongly suggest that eNOS is a source of ROS in these cells. Although BH4 levels were increased as compared with another endothelial cell line, eNOS levels were >2 orders of magnitude higher. The addition of BH4 resulted in increased NO production and decreased generation of ROS, indicating that bEnd.3 cells produce ROS through eNOS uncoupling because of relative BH4 deficiency. Nevertheless, eNOS-dependent ROS production was not completely abolished by the addition of BH4, suggesting intrinsic superoxide production by eNOS. This study indicates that potentially beneficial sustained increases in eNOS expression and activity could lead to eNOS uncoupling and superoxide production as a consequence. Therefore, sustained increases of eNOS or VEGF activity should be accompanied by concomitant supplementation of BH4.

In mice, proteinuria and renal inflammatory responses to albumin overload are strain-dependent.

BACKGROUND: The availability of genetically modified mice has increased the need for relevant mouse models of renal disease, but widely used C57BL/6 mice often show resistance to proteinuria. 129/Sv mice are considered more sensitive to certain renal models. Albumin overload, an important model of proteinuric disease, induces marked proteinuria in rats but barely in C57BL/6 mice. We hypothesized that albumin overload would induce more proteinuria in 129S2/Sv than C57BL/6J mice. METHODS: Male and female C57BL/6J and 129S2/Sv mice received bovine serum albumin (BSA) for 11 days. Control groups received saline injections. Injected BSA was immunohistochemically localized to study intrarenal handling of overloaded protein. Renal macrophage infiltration (F4/80 immuno-staining) and glomerular ultrastructure (electron microscopy) were assessed. RESULTS: The BSA-treated groups were similarly hyperproteinemic at Day 11 (D11). Proteinuria differed widely. In C57BL/6J mice, it remained unchanged in females but significantly, though mildly, increased in males (from 3+/-1 to 8+/-2 mg/day, P < 0.05). In 129S2/Sv, proteinuria was marked in both males and females (4+/-1 to 59+/-14, and 0.6+/-0.2 to 29+/-9 mg/day, respectively, both P < 0.01). Proteinuria was accompanied by tubulo-interstitial macrophage infiltration in 129S2/Sv mice. Injected BSA was visualized within glomeruli in both strains and in the urinary space and tubules of 129S2/Sv but not C57BL/6J mice, indicating much greater glomerular leakage in the former. No glomerular macrophages or ultra-structural differences were detected. CONCLUSION: There are major strain differences in the proteinuria and renal inflammatory response of mice to albumin overload, which are not due to structural variation in the filtration barrier but possibly to functional differences in glomerular protein permeability.

Endothelial function in pediatric patients on peritoneal dialysis: the need for data.

Cardiovascular complications are emerging as the primary cause of death for patients with childhood end-stage renal disease. Children with end-stage renal failure are subjected to many of the risk factors for cardiovascular disease identified in adult patients. Dysfunction of the endothelium is presently regarded as a first but reversible step in the development of atherosclerosis. Noninvasive techniques to assess endothelial function have been recently developed and have been proven to predict future mortality in adult patients. These techniques are readily applicable to pediatric patients. Endothelial dysfunction has been demonstrated in children in all stages of renal failure. Data on pediatric patients treated with peritoneal dialysis are currently lacking, however. Considering the abundance of cardiovascular risk factors specific to treatment with peritoneal dialysis, such studies should be initiated.

Gene expression of energy and protein metabolism in hearts of hypertensive nitric oxide- or GSH-depleted mice.

Hypertension demands cardiac synthetic and metabolic adaptations to increased afterload. We studied gene expression in two models of mild hypertension without overt left ventricular hypertrophy using the NO synthase inhibitor nitro-L-arginine (L-NNA) and the glutathione depletor buthionine-S,R-sulfoximine (BSO). Mice were administered L-NNA, BSO, or water for 8 weeks. RNA of left ventricles was pooled per group, reverse transcribed, Cy3 and Cy5 labeled, and hybridized to cDNA microarrays. Normalized log(2) Cy3/Cy5 ratios of > or =0.7 or < or =-0.7 were considered significant. L-NNA and BSO both caused hypertension. Gene expression was regulated in cytoskeletal components in both models, protein synthesis in L-NNA-treated mice, and energy metabolism in BSO-treated mice. Energy metabolism genes shared several common transcription factor-binding sites such as Coup-Tf2, of which gene expression was increased in BSO-treated mice, and COMP-1. Characterization of the left ventricular adaptations as assessed with gene expression profiles reveals differential expression in energy and protein metabolism related to the pathogenetic background of the hypertension.

Arterial stiffness and fetal growth in normotensive pregnancy.

BACKGROUND: Normal pregnancy is characterized by a decrease in peripheral resistance and generalized vasodilation resulting in plasma volume expansion, which is associated with intrauterine growth. Stiffness of the arterial system may be a measure of the degree of plasma volume expansion. Pulse wave velocity (PWV), measured by applanation tonometry, is a validated approach to determine arterial stiffness. Pulse pressure (PP) is considered a surrogate measure for arterial stiffness. The aim of this study was to evaluate the association between arterial stiffness and fetal growth. METHODS: In 50 normotensive pregnancies, carotid-femoral PWV was measured in the third trimester in 30 degrees lateral position. Blood pressure measurements were performed with conventional auscultatory sphygmomanometry. Birth weight centiles and weight centiles at the age of 6 months were recorded. Linear regression models were used for statistical analyses. RESULTS: There was a significant relationship in PWV with both birth weight centiles and catch-up growth after birth, independent of mean arterial pressure (MAP). An increase of 1 m/sec in PWV was associated with a decrease in birth weight centiles by 17.6% and a catch-up of 22.3% in weight centiles after birth. A stronger association was found for pulse pressure and birth weight centiles. An increase of 1 mm Hg was associated with a decrease in birth weight centiles by 1.8%. There was no association between MAP and birth weight centiles. CONCLUSIONS: In normotensive pregnancy arterial stiffness is associated with birth weight centile and catch-up growth after birth, independently from MAP. This suggests that arterial stiffness reflects maternal vascular adaptation to pregnancy better than blood pressure.