In patients with chronic thromboembolic pulmonary hypertension (CTEPH), elevated pulmonary vascular resistance (PVR) is caused by obstruction of proximal and distal pulmonary arteries with thromboemboli, and by pulmonary vascular remodeling due to excessive migration and proliferation of pulmonary vascular smooth muscle (PASMC) and endothelial (PAEC) cells. The thromboemboli attached to the pulmonary vascular wall include a large amount of blood coagulation factors (e.g., thrombin, fibrinogen), which may serve as triggers for vascular remodeling. A rise in cytosolic [Ca2+] in PAEC induced by thrombin increases endothelial permeability, which allows mitogenic factors to penetrate into the vascular media and cause medial hypertrophy. A rise in cytosolic [Ca2+] in PASMC stimulates cell proliferation by upregulating Ca2+- sensitive signaling proteins and transcription factors. By activating receptors in PASMC, the coagulation factors (e.g., thrombin and fibrinogen) also cause increases in cytosolic [Ca2+] by promoting Ca2+ influx through transient receptor potential (TRP) channels. We have recently demonstrated that a) TRP expression is increased and Ca2+ entry through TRP channels is augmented in normal PASMC during proliferation, b) inhibition of TRP expression with siRNA attenuates PASMC proliferation, c) mRNA and protein expression of TRP (e.g., TRPC3/6) is upregulated in PASMC from patients with idiopathic pulmonary arterial hypertension. Based on these data, we hypothesize that abnormally enhanced gene expression of TRP channels in the pulmonary vasculature serves as a predisposition for thromboemboli-mediated pulmonary vascular remodeling in CTEPH patients.
Three specific aims are proposed to test the hypothesis: 1) To examine whether and which TRP channels are transcriptionally upregulated, and whether TRP-encoded store- and receptor-operated cation channels are functionally enhanced, in PASMC isolated from CTEPH patients;2) To examine whether coagulation factors (thrombin nd fibrinogen) increase cytosolic [Ca2+] by activating TRP channels in PASMC and, if so, which TRP channel subunits are functionally regulated by thrombin and fibrinogen;and 3) To examine whether the mitogenic effect of thrombin and fibrinogen depends on increases in cytosolic [Ca2+] due to Ca2+ entry through TRP channels in normal PASMC and is enhanced in PASMC from CTEPH patients.
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