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Curt D Sigmund

Publications and source records attributed to Curt D Sigmund.

At least 55 records · Page 3Linked to original sources
PubMed2004

Characterization of Lef-1 promoter segments that facilitate inductive developmental expression in skin.

Lymphoid Enhancer Factor 1 (Lef-1) is an important developmental transcription factor required for the inductive formation of several epithelial-derived organs including hair follicles. Inductive expression of Lef-1 mRNA is tightly regulated during embryo development, suggesting the involvement of a highly regulated promoter. In vitro analysis of the Lef-1 gene has demonstrated the existence of at least two spatially distinct promoters with multiple transcriptional start sites that are responsive to the canonical Wnt/beta-catenin pathway. Regions of the Lef-1 promoter required for inductive regulation in vivo, however, have yet to be determined. To this end, we utilized LacZ-reporter transgenic mice to define segments of the human Lef-1 promoter capable of reproducing mesenchymal- or epithelial-restricted transcriptional patterns of Lef-1 expression during hair and vibrissa follicle development. These studies have revealed that a 110 bp Wnt/beta-catenin-responsive element, contained within a minimal 2.5 kb Lef-1 promoter, plays an important role in regulating mesenchymal, and potentially epithelial, expression during follicle development in mouse embryos. This 2.5 kb Lef-1 promoter also demonstrated inductive mesenchymal expression during postnatal anagen stage hair-follicle cycling. Additionally, analysis of Lef-1 promoter expression revealed previously uncharacterized regions of endogenous Lef-1 expression seen in the sebaceous glands of vibrissa and hair follicles in transgenic lines harboring the minimal Lef-1 promoter and additional intronic sequences. In summary, these studies have begun to dissect the transcriptional diversity of the human Lef-1 promoter during the hair/vibrissa follicle and sebaceous gland formation.

Animals↗
PubMed2004

Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin.

The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.

Adipose Tissue, Brown↗
PubMed2003

Ganglionic action of angiotensin contributes to sympathetic activity in renin-angiotensinogen transgenic mice.

In addition to central nervous system actions, angiotensin (Ang) II may increase sympathetic nerve activity (SNA) via a direct action on sympathetic ganglia. We hypothesized that sympathetic ganglionic actions of endogenous Ang II contribute to SNA in transgenic mice that overexpress renin and angiotensinogen (R+A+ mice). Renal SNA and arterial pressure were recorded in anesthetized R+A+ and littermate control mice before and after ganglionic blockade, and after additional blockade of angiotensin type 1 (AT1) receptors with losartan. Ganglionic blockade essentially abolished SNA in control mice, but only reduced SNA to 47+/-18% of baseline in R+A+ mice. The residual SNA remaining after ganglionic blockade in R+A+ mice was reduced from 47+/-18% to 8+/-6% of baseline by losartan (P<0.05). The sympathoinhibitory response to losartan was accompanied by an enhanced decrease in arterial pressure in R+A+ mice compared with that observed in control mice. AT1 receptor expression in sympathetic ganglia, as measured by real-time reverse transcription-polymerase chain reaction, was increased approximately 3-fold in R+A+ versus control mice. The results demonstrate that, as anticipated, essentially all of the renal postganglionic SNA in control mice is driven by preganglionic input. The major new finding is that Ang II-evoked ganglionic activity accounts for approximately 40% of total SNA in R+A+ mice. The significant contribution of the direct ganglionic action of Ang II in R+A+ mice likely reflects both increased levels of Ang II and upregulation of AT1 receptors in sympathetic ganglia.

Angiotensin II↗
PubMed2003

Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels.

Calcium ion (Ca2+) influx through voltage-gated Ca2+ channels is important for the regulation of vascular tone. Activation of L-type Ca2+ channels initiates muscle contraction; however, the role of T-type Ca2+ channels (T-channels) is not clear. We show that mice deficient in the alpha1H T-type Ca2+ channel (alpha(1)3.2-null) have constitutively constricted coronary arterioles and focal myocardial fibrosis. Coronary arteries isolated from alpha(1)3.2-null arteries showed normal contractile responses, but reduced relaxation in response to acetylcholine and nitroprusside. Furthermore, acute blockade of T-channels with Ni2+ prevented relaxation of wild-type coronary arteries. Thus, Ca2+ influx through alpha1H T-type Ca2+ channels is essential for normal relaxation of coronary arteries.

Acetylcholine↗
PubMed2003

Identification of a nuclear orphan receptor (Ear2) as a negative regulator of renin gene transcription.

A potent transcriptional enhancer was previously identified upstream of the mouse renin gene. Within the enhancer is a TGACCT direct-repeat motif, required for enhancer activity, that is the consensus sequence recognized by members of the thyroid hormone subfamily of steroid hormone receptors. We previously reported that RAR/RXR bind to this sequence and mediate the induction of renin promoter activity by retinoids. However, gel mobility shift assays clearly show that other as yet unidentified factors also bind to this motif. In order to identify some of these TGACCT binding factors, we screened a yeast one-hybrid cDNA library derived from mouse As4.1 cells. One of these encoded the orphan nuclear receptor Ear2. Recombinant Ear2 was purified from Escherichia coli and an antipeptide antisera was generated. EMSA showed that purified recombinant Ear2 specifically binds the TGACCT direct-repeat motif. Transfection assays showed that Ear2 potently decreases both baseline and retinoid-induced mouse renin promoter activity in a dose-dependent, enhancer-dependent, and sequence-specific manner. Mutations in Ear2, which abolish its binding to the TGACCT motif, also abolish transcriptional repression. Ear2 was identified as a nuclear protein in As4.1 cells, is one of the proteins binding to the TGACCT repeat motif, and its overexpression can repress transcription of the endogenous renin gene in As4.1 cells. These data suggest that Ear2 is a negative modulator of renin gene transcription in As4.1 cells, and that the renin enhancer may actually encode a complex positive and negative regulator of transcription.

Animals↗
PubMed2003

Efficiency of chimeraplast gene targeting by direct nuclear injection using a GFP recovery assay.

Traditional RNA-DNA chimeric oligonucleotides (chimeraplasts), composed of a continuous stretch of RNA and DNA residues in a duplex conformation, have been shown to correct single-base mutations in episomal and genomic DNA both in vitro and in vivo. In the current study, we have compared the efficiency of single-base pair correction between a traditionally designed chimeraplast (covalently linked duplex) and hybrid chimeraplasts (noncovalent duplexes formed from stretches of RNA and DNA nucleotides synthesized individually and hybridized in vitro). Six hybrid chimeraplasts of identical length were constructed with various lengths of target homology and strand location of the desired nucleotide change. These constructs were evaluated for their ability to correct a point mutation in the gene encoding recombinant enhanced green fluorescent protein (eGFP) that rendered the protein nonfluorescent. A plasmid encoding this mutant eGFP gene and a chimeraplast were co-introduced directly into the nuclei of primary fibroblasts by microinjection. As shown by the recovery of eGFP fluorescence, three of the six hybrid chimeraplasts demonstrated the ability to mediate gene correction (0.4-2.4%). Covalent joining of RNA and DNA strands in chimeraplasts was not necessary for correction of DNA mutations. However, the strand placement of the desired nucleotide change and the length of nonhomologous sequences flanking target nucleotides played a crucial role in the efficiency of chimeraplast-mediated gene correction. Despite the ability of certain chimeraplast designs to correct point mutations in episomal plasmids, targeted correction of integrated copies of the mutant eGFP transgene was unsuccessful in primary fibroblasts. These results demonstrate that, although chimeraplasts are fairly effective at targeting episomal DNA in primary cells, further optimization is required to increase the efficiency for targeting integrated genes.

Base Sequence↗
PubMed2003

Untraditional methods for targeting the kidney in transgenic mice.

With the completion of the human genome project and the sequencing of many genomes of experimental models, there is a pressing need to determine the physiological relevance of newly identified genes. Gene-targeting approaches have become an important tool in our arsenal to dissect the significance of genes expressed in many tissues. A wealth of experimental models has been made to assess the role of gene expression in renal function and development. The development of new and informative models is presently limited by the anatomic complexity of the kidney and the lack of cell-specific promoters to target the numerous diverse cell types in that organ. Because of this, new approaches may have to be developed. In this review, we will discuss several untraditional methods to target gene expression to the kidney. These approaches should provide some additional tricks and tools to help in developing additional informative models for studying renal physiology.

Animals↗
PubMed2003

Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen.

We examined the hypothesis that the renin-angiotensin system plays an important role in vascular remodeling (defined as reduced external diameter) during chronic hypertension. We measured pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in transgenic mice that overexpress both human renin and human angiotensinogen and in spontaneously hypertensive mice, a model of chronic hypertension that is thought to develop independently of the renin-angiotensin system. Systemic arterial pressure under conscious conditions was increased by similar amounts in transgenically hypertensive mice (153+/-6 versus 117+/-4 mm Hg in controls; mean+/-SE, P<0.05) and spontaneously hypertensive mice (148+/-5 versus 112+/-5 mm Hg; P<0.05). The external diameter of maximally dilated cerebral arterioles was reduced in transgenically hypertensive mice (52+/-2 versus 66+/-3 micro m; P<0.05), but not in spontaneously hypertensive mice (58+/-4 versus 60+/-4 micro m; P>0.05). The cross-sectional area of the vessel wall was increased in both transgenically hypertensive mice (504+/-53 versus 379+/-37 microm2; P<0.05) and spontaneously hypertensive mice (488+/-40 versus 328+/-38 microm2; P<0.05). During maximal dilatation, the stress-strain curves in cerebral arterioles of transgenically hypertensive mice and spontaneously hypertensive mice were shifted to the right of the curves in corresponding controls, an indication that arteriolar distensibility was increased in the transgenically and spontaneously hypertensive groups. Thus, cerebral arterioles undergo remodeling and hypertrophy in transgenically hypertensive mice, but only hypertrophy in spontaneously hypertensive mice. These findings support the hypothesis that the renin-angiotensin system is an important determinant of vascular remodeling during chronic hypertension.

Angiotensinogen↗
PubMed2003

Minireview: overview of the renin-angiotensin system--an endocrine and paracrine system.

Since the discovery of renin as a pressor substance in 1898, the renin-angiotensin (RAS) system has been extensively studied because it remains a prime candidate as a causative factor in the development and maintenance of hypertension. Indeed, some of the properties of the physiologically active component of the RAS, angiotensin II, include vasoconstriction, regulation of renal sodium and water absorption, and increasing thirst. Initially, its affect on blood pressure was thought to be mediated primarily through the classical endocrine pathway; that is, the generation of blood-borne angiotensin with actions in target tissues. More recently, however, it has become appreciated that a local autocrine or paracrine RAS may exist in a number of tissues, and that these may also play a significant role in regulating blood pressure. Some of the difficulties in studying tissue RAS stem from the limitations of pharmacology in not differentiating between RAS products made systemically from those synthesized locally. However, the development of transgenic animals with highly specific promoters to target the RAS to specific tissues provided important tools to dissect these systems. Thus, this minireview will discuss recent advances in understanding the relationship between endocrine and paracrine (tissue) RAS using transgenic models.

Animals↗
PubMed2002

Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse.

Angiotensinogen (AGT) was the first gene to be genetically linked to hypertension in humans. Analysis of the gene sequence identified a number of polymorphisms, several of which were reported associated with increased blood pressure (BP) or other cardiovascular diseases. One haplotype of the human AGT (hAGT) gene consisting of an allele at the -6 (A vs. G) position in the promoter and the sequence encoding amino acid 235 (Thr vs. Met) attracted the most attention and has been the subject of numerous association studies. In this report, we addressed the physiological relevance of alleles at these two positions using an experimental mouse model system. Transgenic mice were generated by targeting each haplotype [-6G/235Met (GM) and -6A/235Thr (AT)] as a single copy transgene to the mouse hypoxanthine phosphoribosyl transferase locus, allowing direct comparison of the two transgenes in vivo. Our results indicate that both transgenes exhibit the same transcriptional activity and produce similar levels of hAGT protein in the plasma of the transgenic mice. BP analysis was performed in double transgenic mice generated by breeding each hAGT line to mice expressing a human renin gene. A small but significant increase in BP and relative heart weight was demonstrated by mice carrying the GM haplotype. Moreover, compensatory downregulation of endogenous renin expression was more pronounced in mice containing the GM variant. Our findings suggest that the AT and GM haplotypes of the hAGT gene have no effect on gene expression, but may affect the cardiovascular system and the regulation of BP differently.

Angiotensinogen↗
PubMed2002

Structure of cerebral arterioles in cystathionine beta-synthase-deficient mice.

We examined effects of hyperhomocysteinemia on structure and mechanics of cerebral arterioles. We measured plasma total homocysteine (tHcy) and pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in heterozygous cystathionine beta-synthase-deficient (CBS(+/-)) mice and wild-type (CBS(+/+)) littermates that were provided with drinking water that was unsupplemented (control diet) or supplemented with 0.5% L-methionine (high-methionine diet). Plasma tHcy was 5.0+/-1.1 micro mol/L in CBS(+/+) mice and 8.3+/-0.9 micro mol/L in CBS(+/-) mice (P<0.05 versus CBS(+/+) mice) fed the control diet. Plasma tHcy was 17.2+/-4.6 micro mol/L in CBS(+/+) mice and 21.2+/-3.9 micro mol/L in CBS(+/-) mice (P<0.05) fed the high-methionine diet. Cross-sectional area of the vessel wall was significantly increased in CBS(+/-) (437+/-22 micro m(2)) mice fed control diet and CBS(+/+) (442+/-36 micro m(2)) and CBS(+/-) (471+/-46 micro m(2)) mice fed high-methionine diet relative to CBS(+/+) (324+/-18 micro m(2)) mice fed control diet (P<0.05). During maximal dilatation, the stress-strain curves in cerebral arterioles of CBS(+/-) mice on control diet and CBS(+/+) and CBS(+/-) mice on high-methionine diet were shifted to the right of the curve in cerebral arterioles of CBS(+/+) mice on control diet, an indication that distensibility of cerebral arterioles was increased in mice with elevated levels of plasma tHcy. Thus, hyperhomocysteinemia in mice was associated with hypertrophy and an increase in distensibility of cerebral arterioles. These findings suggest that hyperhomocysteinemia promotes cerebral vascular hypertrophy and altered cerebral vascular mechanics, both of which may contribute to the increased incidence of stroke associated with hyperhomocysteinemia.

Animals↗
PubMed2002

Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice.

Increased superoxide is thought to play a major role in vascular dysfunction in a variety of disease states. Superoxide dismutase (SOD) limits increases in superoxide; however, the functional significance of selected isoforms of SOD within the vessel wall are unknown. We tested the hypothesis that selective loss of CuZnSOD results in increased superoxide and altered vascular responsiveness in CuZnSOD-deficient (CuZnSOD(-/-)) mice compared with wild-type (CuZnSOD(+/+)) littermates. Total SOD activity was reduced (P<0.05) by approximately 60% and CuZnSOD protein was absent in aorta from CuZnSOD(-/-) as compared with wild-type mice. Vascular superoxide levels, measured using lucigenin (5 micro mol/L)-enhanced chemiluminescence and hydroethidine (2 micro mol/L)-based confocal microscopy, were increased (approximately 2-fold; P<0.05) in CuZnSOD(-/-) mice as compared with wild-type mice. Relaxation of the carotid artery in response to acetylcholine and authentic nitric oxide was impaired (P<0.05) in CuZnSOD(-/-) mice. For example, maximal relaxation to acetylcholine (100 micro mol/L) was 50+/-6% and 69+/-5% in CuZnSOD(-/-) and wild-type mice, respectively. Contractile responses of the carotid artery were enhanced (P<0.05) in CuZnSOD(-/-) mice in response to phenylephrine and serotonin, but not to potassium chloride or U46619. In vivo, dilatation of cerebral arterioles (baseline diameter=31+/-1 micro m) to acetylcholine was reduced by approximately 50% in CuZnSOD(-/-) mice as compared with wild-type mice (P<0.05). These findings provide the first direct insight into the functional importance of CuZnSOD in blood vessels and indicate that this specific isoform of SOD limits increases in superoxide under basal conditions. CuZnSOD-deficiency results in altered responsiveness in both large arteries and microvessels.

Animals↗
PubMed2002

Glia- and neuron-specific expression of the renin-angiotensin system in brain alters blood pressure, water intake, and salt preference.

The purpose of this study is to examine the regulation of blood pressure and fluid and electrolyte homeostasis in mice overexpressing angiotensin II (Ang-II) in the brain and to determine whether there are significant physiologic differences in Ang-II production in neurons or glia. Therefore, we generated and characterized transgenic mice overexpressing human renin (hREN) under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice expressing human angiotensinogen (hAGT) under the control of the same promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice exhibited the highest hREN mRNA expression in the brain and had undetectable levels of hREN protein in the systemic circulation. In the brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice overexpressing both hREN and hAGT transgenes in either glia or neurons were moderately hypertensive. In the glia-targeted mice, blood pressure could be corrected by intracerebroventricular injection of the Ang-II type 1 receptor antagonist losartan, and intravenous injection of a ganglion blocking agent, but not an arginine vasopressin V1 receptor antagonist, lowered blood pressure. These data suggest that stimulation of Ang-II type 1 receptors in the brain by Ang-II derived from local synthesis of renin and angiotensinogen can cause an elevation in blood pressure via a mechanism involving enhanced sympathetic outflow. Glia- and neuron-targeted mice also exhibited an increase in drinking volume and salt preference, suggesting that chronic overexpression of renin and angiotensinogen locally in the brain can result in hypertension and alterations in fluid homeostasis.

Animals↗
PubMed2002

Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen.

This study examined vascular function and the role of superoxide in mice that chronically express human renin (R+) and human angiotensinogen (A+). Responses of aortas from R+/A+ mice and from their normotensive littermates (RA- mice) were examined in vitro. Endothelium-dependent relaxation to acetylcholine was impaired in vessels from R+/A+ mice (e.g., maximal relaxation to 100 microM acetylcholine was 45 +/- 5% and 65 +/- 3% in R+/A+ and RA- mice, respectively; P < 0.05). Relaxation was also impaired to the endothelium-independent dilators authentic nitric oxide and nitroprusside in vessels from R+/A+ mice. Maximal vasorelaxation to the endothelium-independent, non-nitric oxide dilator papaverine was similar in R+/A+ and RA- mice. Incubation of vessels from R+/A+ mice with Tiron (1 mM), a superoxide scavenger, improved relaxation to acetylcholine, nitric oxide, and nitroprusside. In contrast, incubation with diethyldithiocarbamate (1 mM), an inhibitor of copper-containing SODs, reduced acetylcholine- and nitroprusside-induced relaxation in vessels from both R+/A+ and RA- mice. Basal superoxide levels, measured with lucigenin-enhanced chemiluminescence (5 microM lucigenin) and hydroethidine-based fluorescent confocal microscopy, were higher in vessels from R+/A+ mice and were Tiron and polyethylene glycol-SOD sensitive. These results suggest that increased superoxide contributes to impaired nitric oxide-mediated relaxation in this genetic model of chronic angiotensin II-dependent hypertension.

Acetylcholine↗
PubMed2002

A reliable and efficient method for deleting operational sequences in PACs and BACs.

P1-derived artificial chromosomes (PACs) and bacterial artificial chromosomes (BACs) have become very useful as tools to study gene expression and regulation in cells and in transgenic mice. They carry large fragments of genomic DNA (> or =100 kb) and therefore may contain all of the cis-regulatory elements required for expression of a gene. Because of this, even when inserted randomly in the genome, they can emulate the native environment of a gene resulting in a tightly regulated pattern of expression. Because these large genomic clones often contain DNA sequences which can manipulate chromatin at the local level, they become immune to position effects which affect expression of smaller transgenes, and thus their expression is proportional to copy number. Transgenic mice containing large BACs and PACs have become excellent models to examine the regulation of gene expression. Their usefulness would certainly be increased if easy and efficient methods are developed to manipulate them. We describe herein a method to make deletion mutations reliably and efficiently using a novel modification of the Chi-stimulated homologous recombination method. Specifically, we generated and employed a Lox511 'floxed' CAM resistance marker that first affords selection for homologous recombination in Escherichia coli, and then can be easily deleted leaving only a single Lox511 site as the footprint.

Bacteriophage P1↗
PubMed2002

Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite.

The brain renin-angiotensin system (RAS) has an important role in the regulation of cardiovascular function. In the brain, angiotensinogen (AGT) is expressed mainly in astrocytes (glia) and in some neurons in regions controlling cardiovascular activities. Because of the inability to dissect the functional role of astrocyte- vs. neuron-derived AGT in vivo by pharmacological approaches, the exact role of neuron-derived AGT in the regulation of blood pressure (BP) and fluid and electrolyte balance remains unclear. Therefore, we generated a transgenic mouse model overexpressing human AGT under the control of a neuron-specific (synapsin I) promoter (SYN-hAGT). These mice exhibited high-level expression of human AGT mRNA in the brain, with lower expression in the kidney and heart. Human AGT was not detected in plasma, but in the brain it was expressed exclusively in neurons. Intracerebroventricular (30 ng) but not intravenous (500 ng) injection of purified human renin (hREN) caused a pressor response, which was prevented by intracerebroventricular preinjection of the angiotensin II type 1 receptor antagonist losartan, indicating an AT(1) receptor-dependent functional role of neuron-derived AGT in the regulation of BP in response to exogenous REN. Double transgenic mice expressing both the hREN gene and SYN-hAGT transgene exhibited normal BP and water intake but had an increased preference for salt. These data suggest that neuronal AGT may play an important role in regulating salt intake and salt appetite.

Angiotensinogen↗
PubMed2002

Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice.

To examine the physiological importance of brain angiotensin II type 1 (AT1) receptors, we developed a novel transgenic mouse model with rat AT1a receptors targeted selectively to neurons of the central nervous system (CNS). A transgene consisting of 2.8 kb of the rat neuron-specific enolase (NSE) 5' flanking region fused to a cDNA encoding the full open-reading frame of the rat AT1a receptor was constructed and transgenic mice (NSE-AT1a) were generated. Two of six transgenic founder lines exhibited brain-selective expression of the transgene at either moderate or high levels. Immunohistochemistry revealed widespread distribution of AT1 receptors in neurons throughout the CNS. This neuron-targeted overexpression of AT1a receptors resulted in enhanced cardiovascular responsiveness to intracerebroventricular (ICV) angiotensin II (Ang II) injection but not to other central pressor agents, demonstrating functional overexpression of the transgene in NSE-AT1a mice. Interestingly, baseline blood pressure (BP) was not elevated in either transgenic line. However, blockade of central AT1 receptors with ICV losartan caused significant falls in basal BP in NSE-AT1a mice but had no effect in nontransgenic controls. These results suggest that whereas there is an enhanced contribution of central AT1 receptors to the maintenance of baseline BP in NSE-AT1a mice, particularly effective baroreflex buffering prevents hypertension in this model. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT1a receptors in cardiovascular homeostasis in health and disease.

Angiotensin II↗