Involvement of cysteinyl leukotriene receptors in angiogenesis in rat thoracic aortic rings.

Cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators that induce inflammation through the activation of CysLT1 and CysLT2 receptors. It has been reported that inflammatory mediators, such as prostaglandins, play an important role in angiogenesis. However, whether CysLTs and the receptor subtypes are involved in angiogenesis is not clarified. Here, we determined the effects of CysLT receptor agonist leukotriene D4 (LTD4) and antagonists on angiogenesis by rat thoracic aortic ring assay. We found that the microvessel growth in 25% serum-containing cultures was significantly inhibited by the CysLT1 receptor antagonist montelukast (0.1-1 microM), but not by the CysLT2 receptor antagonist BAY cyslt2 (0.1-1 microM). The microvessel growth in serum-free culture was affected neither by montelukast (0.01-1 microM) nor by BAY cyslt2 (0.1-1 microM). Furthermore, LTD4 at 100 nM significantly enhanced the microvessel growth in serum-free culture and LTD4 at 10-100 nM significantly enhanced the microvessel growth in 25% serum-containing cultures. The enhancement was abrogated by both montelukast and BAY cyslt2. Thus, CysLT1 receptors may mediate endogenously regulated microvessel growth in normal culture; whereas the exogenous agonist LTD4 induces angiogenesis through the activation of both CysLT1 and CysLT2 receptors. The CysLT receptor antagonists can be developed as angiogenesis inhibitors.