Collagen and elastin cross-linking: a mechanism of constrictive remodeling after arterial injury

1 INSERM E0016, Faculté de Médecine Paris V, Université René Descartes, Paris; 2 Department of Cardiology and 5 Laboratoire Central de Biochimie, Hôpital Robert Debré, and 4 INSERM ERM 0203 and IFR 53, Reims, France; and 3 Experimental Cardiology Laboratory, University Medical Center, Utrecht, The Netherlands Submitted 28 April 2005 ; accepted in final form 31 May 2005 Constrictive remodeling after arterial injury is related to collagen accumulation. Cross-linking has been shown to induce a scar process in cutaneous wound healing and is increased after arterial injury. We therefore evaluated the effect of cross-linking inhibition on qualitative and quantitative changes in collagen, elastin, and arterial remodeling after balloon injury in the atherosclerotic rabbit model. Atherosclerotic-like lesions were induced in femoral arteries of 28 New Zealand White rabbits by a combination of air desiccation and a high-cholesterol diet. After 1 mo, balloon angioplasty was performed in both femoral arteries. Fourteen rabbits were fed -aminopropionitrile ( -APN, 100 mg/kg) and compared with 14 untreated animals. The remodeling index, i.e., the ratio of external elastic lamina at the lesion site to external elastic lamina at the reference site, was determined 4 wk after angioplasty for both groups. Pyridinoline was significantly decreased in arteries from -APN-treated animals compared with controls, confirming inhibition of collagen cross-linking: 0.30 (SD 0.03) and 0.52 (SD 0.02) mmol/mol hydroxyproline, respectively ( P = 0.002). Scanning and transmission electron microscopy showed a profound disorganization of collagen fibers in arteries from -APN-treated animals. The remodeling index was significantly higher in -APN-treated than in control animals [1.1 (SD 0.3) vs. 0.8 (SD 0.3), P = 0.03], indicating favorable remodeling. Restenosis decreased by 33% in -APN-treated animals: 32% (SD 16) vs. 48% (SD 24) ( P = 0.02). Neointimal collagen density was significantly lower in -APN-treated animals than in controls: 23.0% (SD 3.8) vs. 29.4% (SD 4.0) ( P = 0.004). These findings suggest that collagen and elastin cross-linking plays a role in the healing process via constrictive remodeling and restenosis after balloon injury in the atherosclerotic rabbit model. angioplasty; -aminopropionitrile Address for reprint requests and other correspondence: A. Lafont, Hôpital Européen Georges Pompidou, Service de cardiologie. 20, rue Leblanc, 75340 Paris Cedex 07, France (E-mail: lafont