Systemically administered thrombin inhibitors can prevent neointimal formation and cerebral vasospasm: The possible role of thrombin and PDGF-BB in vascular pathogeneses

Abstract

Thrombin and the complement system are activated in vascular lesions during the process of atherosclerosis or pathologic proliferation of smooth muscle cells, and in the subarachnoid space during the development of cerebral vasospasm following subarachnoid hemorrhage (SAH). This article reviews the effects of a potent inhibitor of the complement system and/or thrombin on vascular neointimal formation in the carotid artery of rats, and the development of cerebral vasospasm following subarachnoid hemorrhage (SAH) in rabbits. Carotid balloon dilation injury induced in rats was treated with FUT-175 for 7 days. In rabbits, SAH was treated with FUT-175, or argatroban for 48 h. In addition, recombinant PDGF-BB was injected into the cisterna magna of normal rabbits to observe the calibers of the basilar arteries for 48 h. Neointimal formation after balloon injury was significantly reduced by the treatment with FUT-175. Development of cerebral vasospasm was prevented by FUT-175 or argatroban. In the histological examination, effective doses of FUT-175 or argatroban suppressed the expression of PDGF-BB in the neointimal lesions. Exogenous PDGF-BB resulted in delayed and prolonged vasoconstriction in normal basilar arteries. The complement system and/or thrombin activation following balloon dilation injury or SAH was demonstrated to play a critical role in the development of vascular lesion formation. In the cascade downstream of the protease activation, the production of PDGF-BB was indicated.