Sequential patterns of chemokine- and chemokine receptor-synthesis following vessel wall injury in porcine coronary arteries
Introduction
Inflammation plays a key role in vascular repair, neointima formation and restenosis [1], [2]. Systemic leukocyte depletion with attenuated mononuclear cell recruitment reduces neointimal volume [3], [4]. As to specific leukocyte subtypes, work from our group previously showed neutrophil granulocyte and macrophage infiltration throughout extensive perivascular coronary tissue post-angioplasty [5], and vascular dendritic cells were identified as a novel cell type in rodent and human neointimal lesions [6], [7]. Although increasing evidence suggests a coordinated recruitment of inflammatory cell populations as a prerequisite for vascular healing, the determinants that induce and sustain this process are incompletely understood. Analyzing mechanisms responsible for the phase-specific and spatially differential chemotaxis of leukocytes and other vascular cells is essential for understanding coronary healing and neointima formation.
Inflammatory cell extravasation and tissue homing depend on chemoattractants such as chemokines (CK), cytokines that induce directed basal and inflammatory leukocyte chemotaxis, gene transcription, proliferation, and apoptosis [8], [9]. Chemokines interact with seven-transmembrane G protein-coupled chemokine receptors (CKR) in a complex, partly overlapping system of >50 ligands and >20 receptors identified to date [9]. Endothelial cells (ECs), smooth muscle cells (SMCs), stromal cells, and epithelial cells can also express chemokines and their receptors, indicating that these cell types are sensitive to specific chemokine signaling [8], [9], [10], [11]. Chemokines like CCL2 and -11, CXCL8, -9, -10, -11, and -12, as well as chemokine receptors like CCR2 and -3, and CXCR2 have been located in atherosclerotic plaques [12], [13], [14], [15], [16], [17]. CCL2 and -11, CXCL8, CCR2 and -3 and others were described following vascular injury [18], [19], [20]. However, the exact time course and transmural arterial localization of chemokine and chemokine receptor expression after angioplasty has not been described in detail.
In the present study, we hypothesized that distinct transmural and perivascular expression patterns of selected chemokines and chemokine receptors implicated in granulocyte, macrophage, and progenitor cell recruitment should be distinguishable after porcine coronary balloon angioplasty. Our findings provide novel insights into coronary inflammatory cell chemotaxis that is essential to ensure a coordinated inflammatory process, and thereby initiates and modulates vascular repair.
Section snippets
Porcine coronary angioplasty
Balloon overstretch injury was performed in left anterior descending and circumflex coronary arteries of female domestic pigs (n = 28; 25–35 kg; Clemson University, Clemson, SC) [5], [21]. Animals were sedated by an intramuscular injection of ketamine (20 mg/kg), xylazine (2 mg/kg), and atropine (0.05 mg/kg). Thiopental (10 mg/kg) was administered intravenously, and general anesthesia was maintained with 1.0–1.5% isoflurane. At 2, 4, and 24 h, 2, 3, 7, or 14 days, animals were sacrificed with an
Results
Porcine coronary arteries were examined at 2, 4, and 24 h, 2, 3, 7, and 14 days after balloon overstretch injury (Table 2). Inflammatory cell aggregation was maximal adjacent to medial injury, and occurred in perivascular tissue (Fig. 1, Table 3). MPO immunostaining was seen in cells with typical neutrophil granulocyte appearance, predominantly located in adventitial and adjacent perivascular areas at 2, 4, and 24 h (Fig. 1A, Table 3). Macrophages, identified by HB141/142 immunostaining and by c-
Discussion
This study demonstrates the transmural and perivascular expression patterns of the chemokines CCL2 and CXCL2 and the chemokine receptors CCR2, CCR5, and CXCR4 following porcine coronary angioplasty. Perivascular tissue is identified as the primary source of the inflammatory leukocyte chemoattractant CCL2 and abundantly contains cells that express chemokine receptors early post-angioplasty. Inflammatory cytokine expression predominantly occurs in granulocytes, macrophages, and myofibroblasts (
Acknowledgements
Supported, in part, by NIH (National Institutes of Health, Bethesda, MD, USA) grant HL57908 (to J.N.W.) and a German Cardiac Society (Duesseldorf, Germany) postdoctoral scholarship (to A.J.). The authors would like to thank Giji Joseph and Tracey Couse for their expert technical assistance.
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Present address: Department of Medicine II, Director: Prof. Dr. T. Munzel, Johannes Gutenberg-University, Mainz, Germany