Blockade of Keratinocyte-Derived Chemokine Inhibits Endothelial Recovery and Enhances Plaque Formation After Arterial Injury in ApoE-Deficient Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 24; no. 10; pp. 1891 - 1896
• Main Authors: Liehn, Elisa A, Schober, Andreas, Weber, Christian
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.10.2004; Hagerstown, MD Lippincott
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Apolipoproteins E - deficiency; Apolipoproteins E - physiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Arteries - pathology; Carotid Arteries - surgery; Chemokines - antagonists & inhibitors; Chemokines - biosynthesis; Chemokines - immunology; Chemokines - physiology; Coronary heart disease; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelium, Vascular - pathology; Endothelium, Vascular - physiology; Endothelium, Vascular - surgery; Heart; Hyperplasia - pathology; Keratinocytes - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic - physiology; Tunica Intima - pathology; Tunica Intima - physiology; Tunica Intima - surgery; Wound Healing - physiology; reendothelialization; Rodentia; Cardiovascular disease; Vascular disease; Chemokine; Restenosis; Vertebrata; Mammalia; Mouse; Animal; Atherosclerosis; Keratinocyte; injury
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000143135.71440.75

OBJECTIVE—We evaluated the involvement of keratinocyte-derived chemokine (KC) in neointimal hyperplasia and endothelial repair after arterial injury. METHODS AND RESULTS—Expression of KC was detected by immunohistochemistry in carotid arteries of apolipoprotein E–deficient (apoE−/−) mice not earlier than 2 weeks after wire-injury. Double immunofluorescence staining revealed a colocalization of KC with Mac-2–positive macrophages. Immunoreactivity for KC and its receptor CXCR2 was detectable in regenerating CD31-positive endothelial cells. Treatment of apoE−/− mice with a blocking monoclonal antibody (mAb) to KC after carotid injury for 3 weeks substantially increased neointimal plaque area compared with isotype control-treated or untreated mice. As assessed by luminal CD31 or VE-cadherin and Evans blue staining, neutralization of KC inhibited endothelial recovery in injured arteries, whereas macrophage and smooth muscle cell content were unaffected. In vitro, treatment with KC mAb, a blocking CXCR2 mAb, or the CXCR2 antagonist 8-73GRO-α delayed KC-mediated endothelial cell chemotaxis and wound repair of endothelial monolayers after scratch injury. Conversely, addition of exogenous KC accelerated wound repair in a CXCR2-dependent manner. CONCLUSIONS—Neutralization of KC increased plaque formation and delayed endothelial recovery after arterial injury, without affecting neointimal monocyte infiltration. As an underlying mechanism, KC was involved in promoting CXCR2-mediated endothelial chemotaxis and wound repair.