Effects of tamoxifen on ischemia-induced angiogenesis in the mouse lung.

Obstruction of pulmonary blood flow in the mouse lung causes a prompt angiogenic response, with new systemic vessels from intercostal arteries penetrating the pleura within 5-6 days [Mitzner et al. Am J Pathol 2000; 157(1): 93-101]. Tamoxifen, a triphenylethylene antiestrogen, has been shown to be effective in limiting tumor growth, possibly because of inhibition of angiogenesis. We investigated the effects of tamoxifen on blood vessel development after left pulmonary artery ligation (LPAL). Timed-release pellets of either tamoxifen (free base/15 mg over 21 days) or placebo carrier were implanted subcutaneously in male C57BL/6J mice 6-8 weeks of age. Two days after pellet implantation, the left pulmonary artery was permanently obstructed by suture ligation. New systemic vessel growth was assessed after left ventricular injection of fluorescence labeled microspheres. Tamoxifen slowed the formation of functional blood vessels seven days after LPAL. By 14 days, however, no difference was observed between tamoxifen and placebo treated mice with systemic perfusion to the left lung reaching a maximum of 3.8% and 4.7% of cardiac output respectively. No change in VEGF mRNA expression was observed until 14 days after LPAL when a small increase (2-fold) was observed in both placebo and tamoxifen treated lungs. However, VEGF protein was elevated in both tamoxifen and placebo lungs 24 h after LPAL (approximately 4-fold). These changes in VEGF protein may be due to the presence of trapped inflammatory cells observed in lung sections at this early time point. Although tamoxifen appeared to slow the progression of blood vessel formation, it did not affect VEGF mRNA, therefore likely acting through an estrogen receptor-independent mechanism.