Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide

Sabrane, Karim; Kruse, Markus N.; Fabritz, Larissa; Zetsche, Bernd; Mitko, Danuta; Skryabin, Boris V.; Zwiener, Melanie; Baba, Hideo A.; Yanagisawa, Masashi; Kühn, Michaela

doi:10.1172/jci23360

Cited by 146 publications

(166 citation statements)

References 46 publications

(80 reference statements)

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“…Hematocrit for both genotypes was in the upper normal range 30 and was not different between AtrapϪ/Ϫ and ϩ/ϩ mice, as reported before for other models of chronic volume expansion. 31,32 PRC and, by inference, renin secretion were suppressed in AtrapϪ/Ϫ mice. The absence of Atrap from renin-generating granular cells of the afferent arteriole indicates the operation of an indirect effect on renin secretion in AtrapϪ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 84%

Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

Oppermann¹,

Gess

Schweda

et al. 2010

Journal of the American Society of Nephrology

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The angiotensin receptor-associated protein (Atrap) interacts with angiotensin II (AngII) type 1 (AT1) receptors and facilitates their internalization in vitro, but little is known about the function of Atrap in vivo. Here, we detected Atrap expression in several organs of wild-type mice; the highest expression was in the kidney where it localized to the proximal tubule, particularly the brush border. There was no Atrap expression in the renal vasculature or juxtaglomerular cells. We generated Atrap-deficient (AtrapϪ/Ϫ) mice, which were viable and seemed grossly normal. Mean systolic BP was significantly higher in AtrapϪ/Ϫ mice compared with wild-type mice. Dose-response relationships of arterial BP after acute AngII infusion were similar in both genotypes. Plasma volume was significantly higher and plasma renin concentration was markedly lower in AtrapϪ/Ϫ mice compared with wild-type mice.125 I-AngII binding showed enhanced surface expression of AT1 receptors in the renal cortex of AtrapϪ/Ϫ mice, accompanied by increased carboanhydrase-sensitive proximal tubular function. In summary, AtrapϪ/Ϫ mice have increased arterial pressure and plasma volume. Atrap seems to modulate volume status by acting as a negative regulator of AT1 receptors in the renal tubules.

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Section: Discussionmentioning

confidence: 84%

Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

Oppermann¹,

Gess

Schweda

et al. 2010

Journal of the American Society of Nephrology

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“…Numerous studies have demonstrated the effectiveness of using the Tie2-Cre mice to selectively delete floxed genes in cells of endothelial lineage. [30][31][32] Myelomonocytic-specific deletion of TFPI-K1 was achieved by crossing the TFPI Flox mice with transgenic mice expressing Cre recombinase under control of the LysM promoter (LysM-Cre). The resulting offspring were backcrossed to TFPI Flox homozygosity while maintaining the LysM-Cre transgene (TFPI LysM ).…”

Section: Generation Of Mice With Cell-specific Deletion Of the Tfpi-kmentioning

confidence: 99%

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

White

Johnson

Zarzhevsky

et al. 2010

Blood

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The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI Flox ) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI Tie2 ) and myelomonocytic (TFPI LysM ) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI Tie2 (71% ؎ 0.9%, P < .001) and TFPI LysM (19% ؎ 0.6%, P < .001) compared with TFPI Flox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI Tie2 mice but not TFPI LysM mice had increased ferric chlorideinduced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial-and myelomonocytic-derived TFPI. (Blood. 2010;116(10):1787-1794) IntroductionThe endothelium provides an antithrombotic interface with circulating blood which is generated in part by the coordinated expression of endothelial-derived anticoagulants. The regulated expression of these endothelial-derived proteins may account in part for differences in thrombotic phenotype among vessels. 1 Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor expressed in endothelial cells and regulates the initiation of coagulation by inhibiting tissue factor (TF)/factor VIIa activation of factor X.TFPI, originally known as lipoprotein associated coagulation inhibitor, was isolated from a hepatoma cell line. 2 TFPI circulates at low (nmol/L) levels in humans largely associated with lipoproteins. 3 Infusion of heparin increases circulating levels of TFPI in humans, and this increase has been attributed to displacement of TFPI from glycosoaminoglycans on the surface of endothelial cells. 4,5 As such, the endothelium has been thought to be the dominant source of circulating TFPI. However, TFPI is also expressed in platelets, vascular smooth muscle, cardiac myocytes, and monocyte/macrophages. 4,[6][7][8][9][10] The physiologic importance of TFPI is confirmed in that no known human deficiencies of TFPI have been reported. Homozygotic deletion of exon 4 in mice (which encodes the Kunitz 1 domain) resulted in embryonic lethality. 11 Heterozygotic deletion results in an increased response to acute and chronic vascular injury. [12][13][14] Conversely, vasculardirected overexpression of TFPI attenuates this response. 15 To better define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis, we generated mice with endothelial and monocytic-restricted deletion of exon 4, which encodes for the TFPI-K1 domain. We also used bone marrow transplantation as a means to generate ...

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“…Utilizing a similar strategy, Sabrane, Kuhn, and coworkers have now used a loxP/Tie2-Cre recombination system to selectively delete the gene for GC-A in mouse vascular endothelium (6). The authors show that the direct vasodilating effects of ANP on isolated arteries and apparently normal renal function were preserved in endothelial cell-specific GC-A knockout mice; however, the animals still exhibited a hypertensive phenotype with expanded vascular volume and cardiac hypertrophy.…”

Section: Renal Versus Endothelial Mechanisms In Regulating Plasma Volumementioning

confidence: 99%

Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume

Curry¹

2005

Journal of Clinical Investigation

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Atrial natriuretic peptide (ANP) acts acutely to reduce plasma volume by at least 3 mechanisms: increased renal excretion of salt and water, vasodilation, and increased vascular permeability. Authors of a study in this issue of the JCI performed a knockout of the receptor for ANP in vascular endothelia in order to distinguish the effects of ANP-dependent increases in vascular permeability from those of other endocrine actions of ANP in the regulation of plasma volume (see the related article beginning on page 1666). The knockout mice exhibited reduced vascular permeability to plasma protein, resulting in chronically increased plasma volume, arterial hypertension, and cardiac hypertrophy. Renal excretion and vasodilation did not account for these changes. Thus ANP-induced increases in endothelial permeability may be critical to the ability of ANP to lower arterial blood pressure. Renal versus endothelial mechanisms in regulating plasma volumePlasma volume is maintained by the interplay of mechanisms regulating total extracellular fluid volume and Starling forces, the latter of which govern the distribution of the extracellular fluid volume between the vascular space and the interstitial space (1). For example, atrial natriuretic peptide (ANP) is a small peptide secreted by the heart upon atrial stretch and high systemic blood pressure. The acute effects of this potent, shortlived peptide include increased glomerular filtration and increased renal excretion of sodium and water. These changes may serve to decrease blood volume and subsequently lower blood pressure (2, 3). However, if these renal responses were the primary effects of ANP action, the loss of tubular fluid derived from glomerular filtration of plasma would concentrate the plasma proteins in the vascular space. The resultant increase in the osmotic pressure of the plasma protein concentration would favor reabsorption of fluid across the endothelial barrier from the interstitial space. Thus, the tendency of ANPdependent renal mechanisms to decrease plasma volume would be opposed by the change in Starling forces, which would tend to increase plasma volume.In addition to these renal effects, ANP causes both vasodilation, by relaxing vascular smooth muscle, and an acute increase in vascular permeability via receptors on the microvascular endothelium (4, 5). These mechanisms also decrease blood volume by favoring redistribution of plasma protein and fluid from the vascular space to the interstitial space. Thus, a key question concerning the role of ANP in the regulation of plasma volume is the relative importance of the renal versus the nonrenal actions of ANP. Renkin and Tucker (5) argued that the extrarenal actions of ANP enable it to preferentially regulate plasma volume. The study reported by Sabrane, Kuhn, and colleagues in this issue of the JCI (6) provides new data to support this hypothesis by investigating the regulation of plasma volume in transgenic mice in which one of the common receptors for ANP has been selectively deleted in vascular endothe...

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Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide

Cited by 146 publications

References 46 publications

Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume

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