Hypoxia-mediated alterations in adenosine receptor expression in rat lung

Background: Chronic hypoxic exposure induces pulmonary arterial remodeling, resulting in pulmonary hypertension (PAH) and right ventricular hypertrophy. The role of adenosine (Ado) receptors in the pathogenesis of PAH has not been addressed. Aims and objectives: To investigate the role of Ado and Ado receptor signaling in hypoxia-induced pulmonary vascular remodeling. Methods: Sprague Dawley rats were exposed to hypobaric hypoxia (5,000 m altitude) for 1 and 3 weeks. The adenosine receptor expression profile in the normoxic and hypoxic rat lungs as well as in rat pulmonary artery and microvascular endothelial cells was determined by real time PCR. Ado receptor agonist treated and untreated endothelial cell (EC) proliferation was determined using CyQuant cell proliferation kit. Results: All four Ado receptors were expressed in the lung tissue. The A2A receptor was the most abundant. The 1 week hypoxic exposure significantly upregulated A1 receptor expression indicating it's role in the adaptive response to hypoxia. The pulmonary arterial pressure (PAP) were significantly elevated after 3 weeks of hypoxia (33±2.3 versus 18±2.3 normoxia). Studies in vitro revealed that Ado receptors are differentially expressed in pulmonary vascular endothelial cells and that treatment with selective adenosine receptor A1 (N6-cyclopentyadenosine) and A3 (HEMADO) agonists affects EC proliferation. Conclusions: The expression profile of the Ado receptors is regulated by hypoxia and targeting adenosine receptors might be promising approach to treat PAH. Funded by AHA 0735388N, FAMRI CIA 072053, Emphysema Research Fund and Bixler Family Foundation.