Detecting thromboxane signaling abnormalities in experimental models of pulmonary arterial hypertension

Abstract

An increased ratio of thromboxane to prostacyclin metabolites has been reported in children and adults with pulmonary arterial hypertension (PAH). Thus, increased thromboxane signaling may contribute to the pathogenesis of PAH. Thromboxane A2 (TXA2) acts on vascular smooth muscle cells to trigger constriction and proliferation. Since the mechanism of enhanced thromboxane signaling has not been elucidated, we designed studies to detect abnormalities of this pathway in two animal models of hypoxia ‐ induced PAH, the neonatal piglet and the adult rat. The Western blot technique revealed a 2.8‐fold increase in the expression of thromboxane synthase in pulmonary arteries (PAs) of neonatal piglets exposed to 3 weeks of hypoxia compared to control neonates exposed to normoxia. Subsequently, we initiated studies to determine if abnormalities of the thromboxane signaling pathway extend to PAs from rat models of adult PAH. This is a preclinical model in which vasodilator therapeutics commonly are tested for efficacy. The expression of the receptor for TXA2, the TP receptor, appeared similar between PAs of adult rats exposed to 5 to 6 weeks of chronic normoxia or hypoxia. Now we are exploring if upstream mediators including an upregulation of thromboxane synthase may contribute to the increased abundance of thromboxane metabolites in adult models of PAH. Supported by UL1RR029884 (ND) and R01 HL083013 (NR) from the NIH.