Deep brain stimulation of the subthalamic nucleus improves non-motor symptoms in Parkinson’s disease, but with considerable inter-individual variability. Petry-Schmelzer et al. show that neurostimulation in specific subregions of the subthalamic nucleus has differential effects on mood/apathy, attention/memory and sleep-related outcomes. Neurostimulation could thus be tailored to patients’ individual non-motor profiles.

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Aims Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Vascular remodeling of pulmonary arteries, characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a hallmark of PAH. Here, we aimed to systematically characterize coagulation-independent effects of key coagulation proteases thrombin and factor Xa (FXa) and their designated receptors, protease-activated receptor (PAR) -1 and -2, on PASMCs in vitro and experimental PH in vivo. Methods and Results In human and murine PASMCs, both thrombin and FXa were identified as potent mitogens, and chemoattractants. FXa mediated its responses via PAR-1 and PAR-2, whereas thrombin signaled through PAR-1. ERK1/2, AKT and sphingonsine kinase-1 were identified as downstream mediators of PAR-1 and PAR-2. Inhibition of FXa or thrombin blunted cellular responses in vitro, but unexpectedly failed to protect against hypoxia-induced PH in vivo. However, pharmacological inhibition as well as genetic deficiency of both PAR-1 and PAR-2 significantly reduced vascular muscularization of small pulmonary arteries, diminished right ventricular systolic pressure and right ventricular hypertrophy upon chronic hypoxia compared to wild type controls. Conclusions Our findings indicate a coagulation-independent pathogenic potential of thrombin and FXa for pulmonary vascular remodeling via acting through PAR-1 and PAR-2, respectively. While inhibition of single coagulation proteases was ineffective in preventing experimental PH, our results propose a crucial role for PAR-1 and PAR-2 in its pathobiology, thus identifying PARs but not their dedicated activators FXa and thrombin as suitable targets for the treatment of PH. Translational Perspective PAH is a currently incurable disease associated with a high mortality if left untreated. The pathogenesis of PAH includes vascular remodeling of small pulmonary arterioles due to aberrant proliferation and migration of PASMCs. FXa and thrombin coagulation-independently induce PASMC proliferation and migration via activation of PAR-1 and PAR-2. However, pharmacological inhibition of FXa or thrombin were largely ineffective, whereas interception at the receptor level, as achieved by deficiency of PAR-1 or PAR-2, robustly reduced the development and progression of experimental PH. Since specific inhibitors are already available, PAR-1 and PAR-2 emerge as novel therapeutic targets in the treatment of PAH.