Identification of Free Nitric Oxide Radicals in Rat Bone Marrow: Implications for Progenitor Cell Mobilization in Hypertension

Krisztian Stadler,Marina A Aleksinskaya,Ton Rabelink,Roeland Hanemaaijer,Jelly Nelissen,Jo G R De Mey,Ernst E H Van Faassen,Ben J A Janssen,Anton Jan Van Zonneveld

doi:10.1371/journal.pone.0057761

Krisztian Stadler, Marina A Aleksinskaya + Show 7 more

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https://doi.org/10.1371/journal.pone.0057761

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Journal: PloS one	Publication Date: Mar 12, 2013
Citations: 53	License type: CC BY 4.0

Affiliation: Leiden University Medical Center, Maastricht University

Abstract

Nitric oxide (NO) has been implicated in matrix metallopeptidase 9 (MMP9)-dependent mobilization of hematopoietic stem and progenitor cells from bone marrow (BM). However, direct measurement of NO in the BM remained elusive due to its low in situ concentration and short lifetime. Using NO spin trapping and electron paramagnetic resonance (EPR) spectroscopy we give the first experimental confirmation of free NO radicals in rodent BM. NO production was quantified and attributed to enzymatic activity of NO synthases (NOS). Although endothelial NOS (eNOS) accounts for most (66%) of basal NO, we identified a significant contribution (23%) from inducible NOS (iNOS). Basal NO levels closely correlate with MMP9 bioavailability in BM of both hypertensive and control rats. Our observations support the hypothesis that inadequate mobilization of BM-derived stem and progenitor cells in hypertension results from impaired NOS/NO/MMP9 signalling in BM, a condition that may be corrected with pharmacological intervention.

Highlights

Proper endothelial function is crucial for vascular homeostasis
endothelial progenitor cells (EPC) have been defined as circulating CD34+ progenitor cells (PC) expressing the kinase insert domain receptor, a minor cell population that constitutes less than 0.004% of the circulating mononuclear cell fraction [7]
Enzymatic generation of Nitric oxide (NO) is detectable in rat bone marrow (BM) NO radicals are implicated in manyphysiological processes, but hard to detect in living tissues due to low concentration and short lifespan

Summary

Introduction

Onset and progression of cardiovascular disease is characterized by an imbalance in the endothelial cell (EC) damage and repair [1]. Lost EC are replaced either by mitotic proliferation of local mature EC and vessel wall-resident stem cells [2], or by the recruitment of endothelial progenitor cells (EPC) from the bone marrow (BM) [3,4]. Given the fact that proliferation of mature EC is fundamentally limited by telomere shortening and cellular senescence [5,6], endothelial monolayer requires constant rejuvenation by EPC. Numerous reports have shown an inverse relation between the number and/or function of circulating CD34+ cells and adverse metabolic and hemodynamic risk factors for cardiovascular disease [8,9,10]

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