Browsing by Subject "P2Y11"

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease with poorly understood pathogenesis. It is characterized by abnormal remodelling of pulmonary vasculature due to uncontrolled apoptosis and proliferation of endothelial (ECs) and smooth muscle cells (SMCs) in vascular wall. In severe PAH pulmonary ECs exhibit hyperproliferative and apoptosis resistant phenotype contributing to the formation of neointima and development of plexiformic lesions. Structural changes promote occlusion of vascular lumen, and thus, increase in pulmonary vascular resistance. To date we lack efficient therapy to prevent vascular remodelling and restore normal vascular function in PAH. Purinergic signalling is potential modulator of pulmonary vascular homeostasis. It comprises of extracellular nucleotides, such as ATP, which signal through their receptors on cell membrane. Ectoenzymes with nucleotide hydrolyzing activity have an essential part in controlling homeostasis and physiologic concentration of extracellular nucleotides. Ectoenzyme CD39 plays a crucial role in dephosphorylating ATP, which is a known mediator of inflammation, angiogenesis, thrombosis and vasoconstriction according to previous research. Aims of this project were to study the role of extracellular ATP in pulmonary endothelial dysfunction during PAH pathogenesis. The goal was to evaluate the significance of ATPases, such as CD39, in the disease process and to identify significant ATP receptors on pulmonary ECs. We utilized a previously unused strategy to monitor ATPase activity in vivo in pulmonary endothelium of rats with PAH. With this strategy we could identify changes in a time-line manner. Our results indicate that ATPase activity is significantly attenuated in ECs during disease process. Similar finding was also observed in human pulmonary EC isolated from PAH patients suggesting that loss of ATPase activity mediated increase of extracellular ATP could play a role in disease pathogenesis. Our in vitro experiments reveal that loss-of CD39 in human pulmonary ECs leads to an apoptosis resistant and hyperproliferative phenotype. We also identify that purinergic receptor P2Y11 is a critical mediator of ATP responses in these ECs. Suppression of ATP mediated P2Y11 response in apoptosis resistant PAH patient ECs restores normal EC phenotype and thus, suggests a novel therapeutic strategy for pulmonary occlusive vasculopathy.