Pulmonary hypertension (PH) is the leading symptom of diseases characterized by an increase in mean pulmonary arterial blood pressure. PH increases right ventricular stress and ultimately leads to potentially fatal right heart failure. Hence, the mean survival time after PH diagnosis is only three years in the absence of therapy. At the histological level, PH is characterized by structural vascular remodeling in the lung that is evident as muscularization of arterioles and hyperproliferation of endothelial cells. Despite extensive research, no causal therapy for PH exists up to now. Rather, approved drugs only delay disease progression, which ultimately ends in most cases with lung transplantation or death. This poor prognosis illustrates the need to investigate underlying molecular pathomechanisms of PH in order to identify causal and targeted treatment strategies.
In an ongoing research project, we identified a potential candidate for such a causal therapy: the primary cilium. The primary cilium is an organelle that extends as a protrusion of the cell membrane into the extracellular space and functions as a chemo- and mechanosensor. In PH, we detected a shortening and loss of the primary cilium in pulmonary artery endothelial and smooth muscle cells by a so far unknown mechanism. Our in vitro experiments show that a respective cilium loss increases proliferation and migration of endothelial and smooth muscle cells. These results identify a dysregulation of the primary cilium in PH, which is expected to contribute to vascular remodeling and thus, disease progression. Hence, therapies promoting cilium elongation or reciliation could possibly slow down or even prevent vascular remodeling and PH. However, the signal pathways regulating the primary cilium in PH are so far unknown.
To address this topic, we aim to investigate first in vitro whether and how candidate-signaling pathways including mTOR, PDGF, TGF-β and NO are regulated by deciliation in pulmonary arterial endothelial and smooth muscle cells. Next, we will test in which way these signaling pathways regulate cell ciliation as well as cellular responses characteristic of PH, including cell proliferation, migration, smooth muscle hypertrophy, and endothelial-to-mesenchymal transition. In a second step, we will test whether cilium elongation by repurposing of already approved drugs may inhibit the activation of these signaling pathways and thus, cellular responses characteristic of PH. Finally, the obtained insights into the regulation of the primary cilium and its effects on cellular responses in PH will be translated to preclinical in vivo models of PH in mice and rats with the aim to develop and validate novel therapeutic treatment strategies for PH. As such, the outcome of the proposed work is expected to yield important new insights into cellular and molecular mechanisms of health and disease, and in parallel to generate tangible improvements in medical care for a fatal illness that can hitherto only be treated symptomatically.