The natriuretic peptide/guanylyl cyclase-A system functions as a stress-responsive regulator of angiogenesis in mice

Kühn, Michaela; Schwarz, Kristine; Hartmann, Michael; Carbajo-Lozoya, Javier; Flögel, Ulrich; Stypmann, Jörg; Eickels, Martin van; Gambaryan, Stepan; Wieland, Thomas; Baba, Hideo A.

doi:10.1186/1471-2210-9-s1-s23

Cited by 30 publications

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“…The ability of ANP to enhance microvascular albumin clearance depends on its binding to the endothelial cGMP producing receptor GC‐A (Kuhn et al . , Kuhn ). The resulting cGMP increase can (i) directly activate PKG, (ii) directly inhibit PDE3 degradation of cAMP and thus indirectly activate PKA and Epac, or (iii) directly activate PDE2 to indirectly lower cAMP and thereby reduce PKA and Epac activity (Surapisitchat et al .…”

Section: Discussionmentioning

confidence: 99%

Increased microvascular permeability in mice lacking Epac1 (Rapgef3)

et al. 2016

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AimMaintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signalling. This study probes the role of the cAMP mediators rap guanine nucleotide exchange factor 3 and 4 (Epac1 and Epac2) for in vivo control of microvascular macromolecule permeability under basal conditions.MethodsEpac1−/− and Epac2−/− C57BL /6J mice were produced and compared with wild‐type mice for transvascular flux of radio‐labelled albumin in skin, adipose tissue, intestine, heart and skeletal muscle. The transvascular leakage was also studied by dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) using the MRI contrast agent Gadomer‐17 as probe.ResultsEpac1−/− mice had constitutively increased transvascular macromolecule transport, indicating Epac1‐dependent restriction of baseline permeability. In addition, Epac1−/− mice showed little or no enhancement of vascular permeability in response to atrial natriuretic peptide (ANP), whether probed with labelled albumin or Gadomer‐17. Epac2−/− and wild‐type mice had similar basal and ANP‐stimulated clearances. Ultrastructure analysis revealed that Epac1−/− microvascular interendothelial junctions had constitutively less junctional complex.ConclusionEpac1 exerts a tonic inhibition of in vivo basal microvascular permeability. The loss of this tonic action increases baseline permeability, presumably by reducing the interendothelial permeability resistance. Part of the action of ANP to increase permeability in wild‐type microvessels may involve inhibition of the basal Epac1‐dependent activity.

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Section: Discussionmentioning

confidence: 99%

Increased microvascular permeability in mice lacking Epac1 (Rapgef3)

et al. 2016

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“…In HUVEC and human coronary arterial endothelial cells, low ANP concentrations stimulated proliferation and migration, whereas high concentrations exerted inhibitory effects (Kook et al ., 2003). Pro‐angiogenic actions of ANP and/or BNP were also observed in bovine aortic endothelia (BAEC) (Chen et al ., 2008) and microvascular endothelia from rat fat pad capillaries (RFPECs) (Kuhn et al ., 2009). Moreover, BNP stimulated the proliferation, adhesion and migration of EPCs (Shmilovich et al ., 2009).…”

Section: Effects Of Anp and Bnp On Endothelial Regeneration And Neovamentioning

confidence: 99%

Endothelial actions of atrial and B‐type natriuretic peptides

Kühn

2012

British J Pharmacology

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The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro-and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the actions of NPs on endothelial permeability and regeneration. AbbreviationsANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; cGKI, cGMP-dependent protein kinase; VASP, vasodilator-stimulated phosphoprotein IntroductionThe heart secretes two natriuretic peptides (NPs), atrial (ANPs) and B-type NPs (BNPs) (de Bold et al., 1981;Brenner et al., 1990), which activate a common GC-A receptor expressed in a wide variety of tissues and cell types (reviewed by Kuhn, 2003). GC-A [also known as NP receptor A (NPR-A)] is a transmembrane receptor with an intracellular GC domain (Alexander et al., 2011). It synthesizes the second messenger cGMP upon binding of the ligands (ANP with~10-fold higher affinity than BNP) to its extracellular part (Figure 1) (Drewett and Garbers, 1994). ANP is secreted from atrial granules into the circulation in response to acute or chronic atrial stretch to physiologically act as antihypertensive and antihypervolaemic factor via GC-A in distant organs (de Bold et al., 2001). In contrast, cardiac BNP is constitutively expressed i...

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“…In addition, BNP also exhibits antifibrotic (8), antihypertrophic (9), anti-inflammatory (10), and angiogenic (11) actions, and acutely opposes the reninangiotensin-aldosterone (12) and sympathetic nervous systems. Various strategies have been attempted to potentiate the beneficial effects of NPs in both ADHF and stable chronic HF (CHF) patients (13).…”

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confidence: 97%