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Pharmacol Res. 2014 Feb;80:43-51. doi: 10.1016/j.phrs.2013.12.008. Epub 2014 Jan 7.

Angiopoietin-1 regulates microvascular reactivity and protects the microcirculation during acute endothelial dysfunction: role of eNOS and VE-cadherin.

Author information

1
Microcirculation Research Group, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, UK. Electronic address: alessio.alfieri@kcl.ac.uk.
2
Kidney Genetics Group, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, UK.
3
Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland.
4
Microcirculation Research Group, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, UK; Kidney Genetics Group, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, UK.
5
Microcirculation Research Group, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, UK.
6
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.

Abstract

The growth factor angiopoietin-1 (Ang-1) plays an essential role in angiogenesis and vascular homeostasis. Nevertheless, the role of Ang-1 in regulating vascular tone and blood flow is largely unexplored. Endothelial nitric oxide synthase (eNOS) and the junctional protein VE-cadherin are part of the complex signalling cascade initiated by Ang-1 in endothelial cells. In this study, we aimed to investigate the mechanisms underlying acute effects of Ang-1 on microvascular reactivity, permeability and blood flow, and hypothesise that eNOS and VE-cadherin underpin Ang-1 mediated vascular effects that are independent of angiogenesis and proliferation. Myography of isolated microarterioles from male C3H/HeN mice (7-10 weeks) was employed to measure vascular reactivity in vitro. Microcirculatory function in vivo was evaluated by intravital microscopy and Doppler fluximetry in dorsal window chambers. Ang-1 and its stable variant MAT.Ang-1 induced a concentration-dependent vasodilation of arterioles in vitro, which was blocked with nitric oxide (NO) synthesis inhibitor l-NAME. In vivo, MAT.Ang-1 restored to control levels l-NAME induced peripheral vasoconstriction, decreased blood flow and microvascular hyperpermeability. Tissue protein expression of VE-cadherin was reduced by NOS inhibition and restored to control levels by MAT.Ang-1, whilst VE-cadherin phosphorylation was increased by l-NAME and subsequently reduced by MAT.Ang-1 administration. Moreover, MAT.Ang-1 alone did not modulate systemic levels of angiogenetic factors. Our novel findings report that Ang-1 induces arteriolar vasodilation via release of NO, suggesting that Ang-1 is an important regulator of microvascular tone. As MAT.Ang-1 ameliorates detrimental effects on the microcirculation induced by inhibition of NO synthesis and stabilizes the endothelial barrier function through VE-cadherin, we propose that this Ang-1 variant may serve as a novel therapeutic agent to protect the microcirculation against endothelial dysfunction.

KEYWORDS:

Angiopoetin-1; Endothelium; Intravital microscopy; Microcirculation; VE-cadherin; eNOS

PMID:
24407281
DOI:
10.1016/j.phrs.2013.12.008
[Indexed for MEDLINE]

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