Over-expression of hepatocyte growth factor in smooth muscle cells regulates endothelial progenitor cells differentiation, migration and proliferation
Introduction
Hepatocyte growth factor (HGF) is a multifunctional cytokine that enhances proliferation [1], [2], [3], motility [4], [5], [6], [7], differentiation [3] and morphogenesis [8] of various cell types and also acts as an anti-apoptotic factor [9]. Due to its mitogenic and anti-apoptotic action on endothelial cells (ECs), HGF seems to play an important role in ECs regeneration [10] and therefore might have a protective function in the complex process of atherogenesis. In animal studies, transfection of HGF gene into balloon-injured carotid artery induced therapeutic angiogenesis, inhibited neointima formation and promoted re-endothelialization [10]. The role of HGF in smooth muscle cells (SMCs) is controversial. Huang et al. demonstrated that incubation of cultured coronary SMCs with HGF did not significantly alter SMCs migration and that a decrease rather than an increase of HGF synthesis in coronary SMCs might promote coronary atherosclerosis [11]. In contrast, some other studies suggested that HGF might induce SMCs migration and proliferation and promote the development of atherosclerotic lesions and plaque destabilization [6], [7]. These data suggest that HGF plays an important role in the processes of endothelial repair and development of atherosclerosis.
Endothelial progenitor cells (EPCs), which derived from hematopoietic stem cells, can mobilize into peripheral blood from bone marrow and home to as well as incorporate into the sites of ischemic tissue or wounded blood vessel wall followed by differentiating into mature ECs and play a crucial role in angiogenesis and endothelial repair [12], [13], [14], [15]. The activity of EPCs can be regulated by many factors such as vascular endothelial growth factor (VEGF) and estrogen [15], [16], [17]. Physical training could induce a significant increase in the circulating EPC number in C57BL/6J mice and the serum VEGF levels were also markedly increased, these effects could be further amplified by l-arginine [18]. HGF is constitutively produced by bone marrow stromal cells and plays a role in the growth and maintenance of hematopoietic progenitors [3], [19]. Exogenous HGF administration could induce VEGF production from SMCs [20]. Previous studies demonstrated that HGF could induce angiogenesis in injured lungs through mobilizing EPCs from bone marrow [12]. However, until now, little is known about the possible role of HGF in modulating EPCs activity. The present study was to check whether over-expression of HGF in SMCs would be helpful for promoting EPCs differentiation and increasing EPCs migration and proliferation.
Section snippets
Isolation and culture of bone-marrow-derived putative EPCs
Male Sprague–Dawley rats (1–2 month-old, provided by Institute of Zoology of Daping Hospital, Third Military Medical university, People's Republic of China) were used to perform this study. The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). EPCs were isolated and cultured according to previously described techniques, which can effectively reduce the number of
Characterization of putative EPCs
Rat bone marrow derived EPCs cultured for 3–4 days appeared to be in a spindle- and cobble-stone shaped morphology (Fig. 1A). After 4 days in culture, the endothelial cell phenotype of EPCs was characterized by double positive (89.93 ± 3.73) % (n = 6) for DiL-ac-LDL uptake (Fig. 1B, red) and lectin binding (Fig. 1B, green). Endothelial phenotypes were confirmed by additional immunostaining of CD31 (Fig. 1C) and eNOS (Fig. 1D). Cell integrity was documented with corresponding nuclear staining. CD45
Discussion
Since Asahara et al. [13] reported that a subtype of hematopoietic progenitor cells from adults, namely “endothelial progenitor cells” (EPCs), showed EC features and could differentiate into mature ECs and might represent a potential strategy for the injured endothelium restoration, experiments performed in different models confirmed that its potent role in vascular restoration and angiogenesis was very encouraging [15], [16]. However, EPCs are a fairly rare cell population, when given
Acknowledgements
The study is supported by grants from National Natural Science Foundation of China (No.30470729 and 30700889) and National Science Foundation of Postdoctoral Research, Xinqiao Hospital, the Third Military Medical University (2005A0122).
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [40].
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