Curt D Sigmund

University of Iowa, Iowa City, Iowa, United States

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Publications (249)1501.21 Total impact

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    ABSTRACT: We tested the hypothesis that endothelial peroxisome proliferator-activated receptor-γ protects against vascular thrombosis using a transgenic mouse model expressing a peroxisome proliferator-activated receptor-γ mutant (E-V290M) selectively in endothelium. The time to occlusive thrombosis of the carotid artery was significantly shortened in E-V290M mice compared with nontransgenic littermates after either chemical injury with ferric chloride (5.1±0.2 versus 10.1±3.3 minutes; P=0.01) or photochemical injury with rose bengal (48±9 versus 74±9 minutes; P=0.04). Gene set enrichment analysis demonstrated the upregulation of NF-κB target genes, including P-selectin, in aortic endothelial cells from E-V290M mice (P<0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290M mice (P<0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290M mice compared with nontransgenic mice (53±8 versus 25±7 per minute; P=0.02). The shortened time to arterial occlusion in E-V290M mice was reversed by administration of P-selectin-blocking antibodies or neutrophil-depleting antibodies (P=0.04 and P=0.02, respectively) before photochemical injury. Endothelial peroxisome proliferator-activated receptor-γ protects against thrombosis through a mechanism that involves downregulation of P-selectin expression and diminished P-selectin-mediated leukocyte-endothelial interactions. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2015; DOI:10.1161/ATVBAHA.115.305378 · 6.34 Impact Factor
  • Pimonrat Ketsawatsomkron, Curt D Sigmund
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    ABSTRACT: This review summarizes recent findings on the regulation of vascular tone by the nuclear receptor transcription factor, peroxisome proliferator activated receptor (PPAR) γ. Much of the recent work utilizes genetic tools to interrogate the significance of PPARγ in endothelial and smooth muscle cells and novel PPARγ target genes have been identified. Endothelial PPARγ prevents inflammation and oxidative stress, while promoting vasodilation by controlling the regulation of NADPH oxidase, catalase and superoxide dismutase gene expression. Moreover, the protective functions of endothelial PPARγ appear more prominent during disease conditions. Novel findings also suggest a role for endothelial PPARγ as a mediator of whole body metabolism. In smooth muscle cells, PPARγ regulates vascular tone by targeting genes involved with contraction and relaxation signaling cascades, some of which is via transcriptional activation, and some through novel mechanisms regulating protein turnover. Furthermore, aberrant changes in renin-angiotensin system components and exacerbated responses to angiotensin II induced vascular dysfunction are observed when PPARγ function is lost in smooth muscle cells. With these recent advances based partially on lessons from patients with PPARγ mutants, we conclude that vascular PPARγ is protective and plays an important role in the regulation of vascular tone.
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    ABSTRACT: Preeclampsia is a cardiovascular disorder of late pregnancy that is, commonly characterized by hypertension, renal structural damage and dysfunction, and fetal growth restriction. Prevailing etiologic models of this disorder include T-cell dysfunction as an initiating cause of preeclampsia. Indoleamine 2,3-dioxygenase (IDO), an enzyme that mediates the conversion of tryptophan to kynurenine, has been linked to preeclampsia in humans, and is known to regulate T-cell activity and an endothelial-derived relaxing factor. To test the hypothesis that IDO is causally involved in the pathogenesis of preeclampsia, mice deficient for IDO (IDO-KO) were generated on a C57BL/6 background. IDO-KO and wild-type C57BL/6 mice were bred, and preeclampsia phenotypes were evaluated during pregnancy. Pregnant IDO-KO mice exhibited pathognomonic renal glomerular endotheliosis, proteinuria, pregnancy-specific endothelial dysfunction, intrauterine growth restriction, and mildly elevated blood pressure compared to wild-type mice. Together these findings highlight an important role for IDO in the generation of phenotypes typical of preeclampsia. Loss of IDO function may represent a risk factor for the development of preeclampsia. By extension, increased IDO activity, reductions in IDO reactants, or increases in IDO products may represent novel therapeutic approaches for this disorder.
    01/2015; 3(1). DOI:10.14814/phy2.12257
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    ABSTRACT: It is critical for cells to maintain a homeostatic balance of water and electrolytes as disturbances can disrupt cellular function which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extra-cellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the MAP kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and Ang II. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 12/2014; 308(4):ajpregu.00486.2014. DOI:10.1152/ajpregu.00486.2014 · 3.53 Impact Factor
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    ABSTRACT: The development of the kidney arterioles is poorly understood. Mature arterioles contain several functionally and morphologically distinct cell types including smooth muscle, endothelial, and juxtaglomerular cells, and they are surrounded by interconnected pericytes, fibroblasts and other interstitial cells. We have shown that the embryonic kidney possesses all the necessary precursors for the development of the renal arterial tree, and those precursors assemble in situ to form the kidney arterioles. However the identity of those precursors was unclear. Within the embryonic kidney, several putative progenitors marked by the expression of either the winged-forkhead transcription factor 1 (Foxd1+ progenitor), the aspartyl-protease renin (Ren+ progenitor), and/or hemangioblasts (Scl+ progenitor) are likely to differentiate and endow most of the cells of the renal arterial tree. However, the lineage relationships and the role of these distinct progenitors in renal vascular morphogenesis have not been delineated. We therefore designed a series of experiments to ascertain the hierarchical lineage relationships between Foxd1+ and Ren+ progenitors and the role of these two precursors in the morphogenesis and patterning of the renal arterial tree. Results show that 1) Foxd1+ cells are the precursors for all the mural cells (renin cells, smooth muscle cells, perivascular fibroblasts and pericytes) of the renal arterial tree and glomerular mesangium and 2) Foxd1 per se directs the origin, number, orientation and cellular composition of the renal vessels. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 11/2014; 308(2):ajpregu.00428.2014. DOI:10.1152/ajpregu.00428.2014 · 3.53 Impact Factor
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    ABSTRACT: Myogenic responses by resistance vessels are a key component of autoregulation in brain, thus playing a crucial role in regulating cerebral blood flow and protecting the blood-brain barrier against potentially detrimental elevations in blood pressure. Although cerebrovascular disease is often accompanied by alterations in myogenic responses, mechanisms that control these changes are poorly understood. Peroxisome proliferator-activated receptor γ has emerged as a regulator of vascular tone. We hypothesized that interference with peroxisome proliferator-activated receptor γ in smooth muscle would augment myogenic responses in cerebral arteries. We studied transgenic mice expressing a dominant-negative mutation in peroxisome proliferator-activated receptor γ selectively in smooth muscle (S-P467L) and nontransgenic littermates. Myogenic tone in middle cerebral arteries from S-P467L was elevated 3-fold when compared with nontransgenic littermates. Rho kinase is thought to play a major role in cerebrovascular disease. The Rho kinase inhibitor, Y-27632, abolished augmented myogenic tone in middle cerebral arteries from S-P467L mice. CN-03, which modifies RhoA making it constitutively active, elevated myogenic tone to ≈60% in both strains, via a Y-27632-dependent mechanism. Large conductance Ca(2+)-activated K(+) channels (BKCa) modulate myogenic tone. Inhibitors of BKCa caused greater constriction in middle cerebral arteries from nontransgenic littermates when compared with S-P467L. Expression of RhoA or Rho kinase-I/II protein was similar in cerebral arteries from S-P467L mice. Overall, the data suggest that peroxisome proliferator-activated receptor γ in smooth muscle normally inhibits Rho kinase and promotes BKCa function, thus influencing myogenic tone in resistance arteries in brain. These findings have implications for mechanisms that underlie large- and small-vessel disease in brain, as well as regulation of cerebral blood flow.
    Hypertension 11/2014; 65(2). DOI:10.1161/HYPERTENSIONAHA.114.04541 · 7.63 Impact Factor
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  • Justin L Grobe, Curt D Sigmund
    Hypertension 09/2014; DOI:10.1161/HYPERTENSIONAHA.114.04075 · 7.63 Impact Factor
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    ABSTRACT: Although peroxisome proliferator-activated receptor-γ (PPARγ) is thought to play a protective role in the vasculature, its cell-specific effect, particularly in resistance vessels, is poorly defined. Nitric oxide (NO) plays a major role in vascular biology in the brain. We examined the hypothesis that selective interference with PPARγ in vascular muscle would impair NO-dependent responses and augment vasoconstrictor responses in the cerebral circulation. We studied mice expressing a dominant negative mutation in human PPARγ (P467L) under the control of the smooth muscle myosin heavy chain promoter (S-P467L). In S-P467L mice, dilator responses to exogenously applied or endogenously produced NO were greatly impaired in cerebral arteries in vitro and in small cerebral arterioles in vivo. Select NO-independent responses, including vasodilation to low concentrations of potassium, were also impaired in S-P467L mice. In contrast, increased expression of wild-type PPARγ in smooth muscle had little effect on vasomotor responses. Mechanisms underlying impairment of both NO-dependent and NO-independent vasodilator responses after interference with PPARγ involved Rho kinase with no apparent contribution by oxidative stress-related mechanisms. These findings support the concept that via effects on Rho kinase-dependent signaling, PPARγ in vascular muscle is a major determinant of vascular tone in resistance vessels and, in particular, NO-mediated signaling in cerebral arteries and brain microvessels. Considering the importance of NO and Rho kinase, these findings have implications for regulation of cerebral blood flow and the pathogenesis of large and small vessel disease in brain.
    Hypertension 09/2014; 64(5). DOI:10.1161/HYPERTENSIONAHA.114.03935 · 7.63 Impact Factor
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    ABSTRACT: Peroxisome proliferator activated receptor γ (PPARγ) has been reported to play a protective role in the vasculature; however, the underlying mechanisms involved are not entirely known. We previously showed that vascular smooth muscle-specific overexpression of a dominant negative human PPARγ mutation in mice (S-P467L) leads to enhanced myogenic tone and increased angiotensin-II-dependent vasoconstriction. S-P467L mice also exhibit increased arterial blood pressure. Here we tested the hypotheses that a) mesenteric smooth muscle cells isolated from S-P467L mice exhibit enhanced angiotensin-II AT1 receptor signaling, and b) the increased arterial pressure of S-P467L mice is angiotensin-II AT1 receptor dependent. Phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (ERK1/2) was robustly increased in mesenteric artery smooth muscle cell cultures from S-P467L in response to angiotensin-II. The increase in ERK1/2 activation by angiotensin-II was blocked by losartan, a blocker of AT1 receptors. Angiotensin-II-induced ERK1/2 activation was also blocked by Tempol, a scavenger of reactive oxygen species, and correlated with increased Nox4 protein expression. To investigate whether endogenous renin-angiotensin system activity contributes to the elevated arterial pressure in S-P467L, non-transgenic and S-P467L mice were treated with the AT1 receptor blocker, losartan (30 mg/kg per day), for 14-days and arterial pressure was assessed by radiotelemetry. At baseline S-P467L mice showed a significant increase of systolic arterial pressure (142.0±10.2 vs 129.1±3.0 mmHg, p<0.05). Treatment with losartan lowered systolic arterial pressure in S-P467L (132.2±6.9 mmHg) to a level similar to untreated non-transgenic mice. Losartan also lowered arterial pressure in non-transgenic (113.0±3.9 mmHg) mice, such that there was no difference in the losartan-induced depressor response between groups (-13.53±1.39 in S-P467L vs -16.16±3.14 mmHg in non-transgenic). Our results suggest that interference with PPARγ in smooth muscle: a) causes enhanced angiotensin-II AT1 receptor-mediated ERK1/2 activation in resistance vessels, b) and may elevate arterial pressure through both angiotensin-II AT1 receptor-dependent and -independent mechanisms.
    PLoS ONE 08/2014; 9(8):e103786. DOI:10.1371/journal.pone.0103786 · 3.53 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined blood pressure and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared to controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400ng/kg/min resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 ± 4 mmHg in KO vs 128 ± 3 mmHg in controls). Urinary renin excretion and remained significantly lower in the KO mice following Ang-II infusion as compared to controls. Further, membrane associated ENaC protein levels were significantly lower in KO mice following Ang-II infusion. These findings suggest that CD renin modulates blood pressure in angiotensin II infused hypertension and these effects are associated with changes in ENaC expression.
    American journal of physiology. Renal physiology 08/2014; 307(8). DOI:10.1152/ajprenal.00367.2014 · 3.30 Impact Factor
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    ABSTRACT: Increased activity of the renin-angiotensin system within the brain elevates fluid intake, blood pressure, and resting metabolic rate. Renin and angiotensinogen are co-expressed within the same cells of the subfornical organ; and the production and action of angiotensin-II through the angiotensin-II type 1 receptor in the SFO is necessary for fluid intake due to increased activity of the brain renin-angiotensin system. We generated an inducible model of angiotensin-II production by breeding transgenic mice expressing human renin in neurons controlled by the synapsin promoter with transgenic mice containing a Cre-recombinase inducible human angiotensinogen construct. Adenoviral delivery of Cre-recombinase causes SFO-selective induction of human angiotensinogen expression. Selective production of angiotensin-II in the SFO results in increased water intake, but did not change blood pressure or resting metabolic rate. The increase in water intake was angiotensin-II type 1 receptor-dependent. When given a choice between water and 0.15M NaCl, these mice increased total fluid and sodium, but not water, because of an increased preference for NaCl. When provided a choice between water and 0.3M NaCl, the mice exhibited increased fluid, water and sodium intake, but no change in preference for NaCl. The increase in fluid intake was blocked by an inhibitor of protein kinase C, but not extracellular regulated kinases, and correlated with increased phosphorylated cyclic AMP response element binding protein in the subfornical organ. Thus increased production and action of angiotensin-II specifically in the subfornical organ is sufficient on its own to mediate an increase in drinking through protein kinase C.
    AJP Regulatory Integrative and Comparative Physiology 06/2014; 307(4). DOI:10.1152/ajpregu.00216.2014 · 3.53 Impact Factor
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    ABSTRACT: Downloaded from 1 P eroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Classically, PPARγ plays an important role in adipogenesis and metabolic processes but has recently emerged as a crucial element in cardiovascular diseases such as hypertension. Mutations of PPARγ lead to hypertension in humans and in experimental animal models.
    Hypertension 06/2014; 64. DOI:10.1161/HYPERTENSIONHA.114.03553 · 7.63 Impact Factor
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    ABSTRACT: S-P467L mice expressing dominant negative peroxisome proliferator-activated receptor-γ selectively in vascular smooth muscle exhibit impaired vasodilation, augmented vasoconstriction, hypertension, and tachycardia. We hypothesized that tachycardia in S-P467L mice is a result of baroreflex dysfunction. S-P467L mice displayed increased sympathetic traffic to the heart and decreased baroreflex gain and effectiveness. Carotid arteries exhibited inward remodeling but no changes in distensibility or stress/strain. Aortic depressor nerve activity in response to increased arterial pressure was blunted in S-P467L mice. However, the arterial pressure and heart rate responses to aortic depressor nerve stimulation were unaltered in S-P467L mice, suggesting that the central and efferent limbs of the baroreflex arc remain intact. There was no transgene expression in nodose ganglion and no change in expression of the acid-sensing ion channel-2 or -3 in nodose ganglion. There was a trend toward decreased expression of transient receptor potential vanilloid-1 receptor mRNA in nodose ganglion, but no difference in the immunochemical staining of transient receptor potential vanilloid-1 receptor in the termination area of the left aortic depressor nerve in S-P467L mice. Although there was no difference in the maximal calcium response to capsaicin in cultured nodose neurons from S-P467L mice, there was decreased desensitization of transient receptor potential vanilloid-1 receptor channels. In conclusion, S-P467L mice exhibit baroreflex dysfunction because of a defect in the afferent limb of the baroreflex arc caused by impaired vascular function, altered vascular structure, or compromised neurovascular coupling. These findings implicate vascular smooth muscle peroxisome proliferator activated receptor-γ as a critical determinant of neurovascular signaling.
    Hypertension 06/2014; 64(3). DOI:10.1161/HYPERTENSIONAHA.114.03553 · 7.63 Impact Factor
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    ABSTRACT: Angiotensin-II production in the subfornical organ acting through angiotensin-II type-1 receptors is necessary for polydipsia, resulting from elevated renin-angiotensin system activity. Protein kinase C and mitogen-activated protein kinase pathways have been shown to mediate effects of angiotensin-II in the brain. We investigated mechanisms that mediate brain angiotensin-II-induced polydipsia. We used double-transgenic sRA mice, consisting of human renin controlled by the neuron-specific synapsin promoter crossed with human angiotensinogen controlled by its endogenous promoter, which results in brain-specific overexpression of angiotensin-II, particularly in the subfornical organ. We also used the deoxycorticosterone acetate-salt model of hypertension, which exhibits polydipsia. Inhibition of protein kinase C, but not extracellular signal-regulated kinases, protein kinase A, or vasopressin V1A and V2 receptors, corrected the elevated water intake of sRA mice. Using an isoform selective inhibitor and an adenovirus expressing dominant negative protein kinase C-α revealed that protein kinase C-α in the subfornical organ was necessary to mediate elevated fluid and sodium intake in sRA mice. Inhibition of protein kinase C activity also attenuated polydipsia in the deoxycorticosterone acetate-salt model. We provide evidence that inducing protein kinase C activity centrally is sufficient to induce water intake in water-replete wild-type mice, and that cell surface localization of protein kinase C-α can be induced in cultured cells from the subfornical organ. These experimental findings demonstrate a role for central protein kinase C activity in fluid balance, and further mechanistically demonstrate the importance of protein kinase C-α signaling in the subfornical organ in fluid intake stimulated by angiotensin-II in the brain.
    Hypertension 04/2014; 64(1). DOI:10.1161/HYPERTENSIONAHA.114.03461 · 7.63 Impact Factor
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    ABSTRACT: The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) is activated by vasoconstrictors in vascular smooth muscle cells (VSMC), but its impact on vasoconstriction remains unknown. We hypothesized that CaMKII inhibition in VSMC decreases vasoconstriction. Using novel transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), we investigated the effect of CaMKII inhibition on L-type Ca(2+) channel current (ICa), cytoplasmic and sarcoplasmic reticulum Ca(2+), and vasoconstriction in mesenteric arteries. In mesenteric VSMC, CaMKII inhibition significantly reduced action potential duration and the residual ICa 50 ms after peak amplitude, indicative of loss of L-type Ca(2+) channel-dependent ICa facilitation. Treatment with angiotensin II or phenylephrine increased the intracellular Ca(2+) concentration in wild-type but not TG SM-CaMKIIN VSMC. The difference in intracellular Ca(2+) concentration was abolished by pretreatment with nifedipine, an L-type Ca(2+) channel antagonist. In TG SM-CaMKIIN VSMC, the total sarcoplasmic reticulum Ca(2+) content was reduced as a result of diminished sarcoplasmic reticulum Ca(2+) ATPase activity via impaired derepression of the sarcoplasmic reticulum Ca(2+) ATPase inhibitor phospholamban. Despite the differences in intracellular Ca(2+) concentration, CaMKII inhibition did not alter myogenic tone or vasoconstriction of mesenteric arteries in response to KCl, angiotensin II, and phenylephrine. However, it increased myosin light chain kinase activity. These data suggest that CaMKII activity maintains intracellular calcium homeostasis but is not required for vasoconstriction of mesenteric arteries.
    Hypertension 06/2013; DOI:10.1161/HYPERTENSIONAHA.113.01508 · 7.63 Impact Factor
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    ABSTRACT: The angiotensinogen gene is genetically linked with hypertension, but the mechanistic basis for association of sequence variants in the promoter and coding region of the gene remains unclear. An E-box at position -20 has been hypothesized to control the level of angiotensinogen expression, but its mechanistic importance for angiotensinogen expression in human tissues is uncertain. We developed an allele-specific polymerase chain reaction-based assay to distinguish between angiotensinogen mRNA derived from variants at the -20 position (rs5050) in the angiotensinogen promoter in adipose tissues obtained during surgery. The assay takes advantage of linkage disequilibrium between the rs5050 (located in the promoter) and rs4762 (located in the coding region) single nucleotide polymorphisms. This strategy allowed us to assess the level of allele-specific expression in A-20C heterozygous subjects comparing the relative proportion of each allele with the total, thus eliminating the problem of variability in the level of total angiotensinogen mRNA among subjects. We show that angiotensinogen mRNA derived from the -20C allele is expressed significantly higher than that derived from the -20A allele in subcutaneous adipose tissue, and increased expression correlates with enriched chromatin binding of upstream stimulatory factor-2 to the -20C E-box compared with -20A. This may be depot selective because we were unable to detect these differences in omental adipose. This provides the first data directly comparing expression of angiotensinogen mRNA and differential transcription factor binding derived from 2 variant alleles in human tissue where the ratio of expression of one allele to another can be accurately determined.
    Hypertension 05/2013; 62(1). DOI:10.1161/HYPERTENSIONAHA.113.01330 · 7.63 Impact Factor
  • Curt D Sigmund
    Arteriosclerosis Thrombosis and Vascular Biology 04/2013; 33(4):676-8. DOI:10.1161/ATVBAHA.112.301125 · 6.34 Impact Factor
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    ABSTRACT: An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4 kDa AVP pro-segment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a non-selective AVP receptor antagonist, Conivaptan (YM-087, 22 ng/hr), or the V2-selective antagonist, Tolvaptan (OPC-41061, 22 ng/hr), resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortae and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V1A receptor mRNA, but no significant changes in V2 receptor expression in kidney were observed. Chronic Tolvaptan infusion also normalized the (5 mmol/L) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS, and suggest a primary role of V2 receptors.
    AJP Regulatory Integrative and Comparative Physiology 03/2013; 304(10). DOI:10.1152/ajpregu.00082.2013 · 3.28 Impact Factor
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    ABSTRACT: Agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) have potent insulin-sensitizing effects and inhibit atherosclerosis progression in patients with type II diabetes. Conversely, missense mutations in the ligand-binding domain of PPARγ that render the transcription factor dominant negative (DN) cause early-onset hypertension and type II diabetes. We tested the hypothesis that DN PPARγ-mediated interference of endogenous wild-type PPARγ in the endothelium and vascular smooth muscle exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Endothelial-specific expression of DN PPARγ on the ApoE-/- background unmasked significant impairment of endothelium-dependent relaxation in aortic rings, increased systolic blood pressure, altered expression of atherogenic markers (e.g. Cd36, Mcp1, Catalase) and enhanced diet-induced atherosclerotic lesion formation in aorta. Smooth muscle-specific expression of DN PPARγ, which induces aortic dysfunction and increased systolic blood pressure at baseline, also resulted in enhanced diet-induced atherosclerotic lesion formation in aorta on the ApoE-/- background that was associated with altered expression of a shared, yet distinct, set of atherogenic markers (e.g. Cd36, Mcp1, Osteopontin, Vcam1). In particular, induction of Osteopontin expression by smooth muscle-specific DN PPARγ correlated with increased plaque calcification. These data demonstrate that inhibition of PPARγ function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease.
    AJP Regulatory Integrative and Comparative Physiology 02/2013; 304(9). DOI:10.1152/ajpregu.00607.2012 · 3.28 Impact Factor

Publication Stats

8k Citations
1,501.21 Total Impact Points


  • 1996–2014
    • University of Iowa
      • • Department of Pharmacology
      • • Department of Internal Medicine
      • • Department of Molecular Physiology and Biophysics
      • • Department of Anatomy and Cell Biology
      • • Department of Pathology
      • • Department of Pediatrics
      Iowa City, Iowa, United States
    • University of Sydney
      Sydney, New South Wales, Australia
  • 2013
    • University of Utah
      Salt Lake City, Utah, United States
  • 1988–2010
    • Roswell Park Cancer Institute
      • Department of Molecular and Cellular Biology
      Buffalo, New York, United States
  • 2006
    • Mayo Foundation for Medical Education and Research
      • Department of Pathology
      Scottsdale, AZ, United States
  • 2004
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1998
    • Weill Cornell Medical College
      New York, New York, United States
  • 1997
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 1995–1997
    • Cornell University
      • Cardiovascular Center
      Ithaca, NY, United States
  • 1984
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States