Upregulation of proteinase-activated receptors and hypercontractile responses precede development of arterial lesions after balloon injury

1 Division of Molecular Cardiology, Research Institute of Angiocardiology; 2 Department of Surgery and Science, Graduate School of Medical Sciences; and 3 Kyushu University Center of Excellence Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan Submitted 13 December 2005 ; accepted in final form 5 July 2006 Thrombin and other proteinases exert vascular effects by activating the proteinase-activated receptors (PARs). The expression of PARs has been shown to be upregulated after balloon injury and in human arteriosclerosis. However, the relationship between the receptor upregulation and the alteration of vasomotor function remains to be elucidated. We herein demonstrated that the contractile responses to the PAR-1 and PAR-2 agonist were markedly enhanced in the rabbit femoral arteries after balloon injury. Neointimal thickening was established 4 wk after the injury. No histological change was observed in the sham operation, where the saphenous artery was ligated without any balloon injury. The contractile response to K + depolarization was significantly attenuated 1 wk after the injury and then partly recovered after 4 wk. Thrombin, PAR-1-activating peptide, trypsin, and PAR-2-activating peptide induced no significant contraction in the control. All these stimulants induced enhanced responses 1 wk after balloon injury. Such enhanced responses were seen 4 wk after the injury, except for thrombin. There was no change in the Ca 2+ sensitivity of the contractile apparatus as evaluated in the permeabilized preparations. PAR-1-activating peptide (100 µmol/l), but no other stimulants, induced an enhanced contraction in the sham operation. The expression of PAR-1 and PAR-2 slightly increased after the sham operation, whereas it markedly and significantly increased after balloon injury. Our observations suggest that balloon injury induced the receptor upregulation, thereby enhancing the contractile response before the establishment of vascular lesions. The local inflammation associated with the sham operation may also contribute to the receptor upregulation. thrombin; protease; vascular tone; vascular injury Address for reprint requests and other correspondence: H. Kanaide, Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu Univ., 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: kanaide{at}molcar.med.kyushu-u.ac.jp )