Abstract
Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1-ATP-TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1-P2Y2R-TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.
Highlights
The pulmonary endothelium exerts a dilatory influence on small, resistance-sized pulmonary arteries (PAs) and thereby lowers pulmonary arterial pressure (PAP)
We postulated that ATP efflux through endothelial pannexin 1 (Panx1) promotes TRPV4EC channel activity
Shear stress-induced increase in luminal Extracellular ATP (eATP) was not altered in PAs from Trpv4 cKO-E C mice compared to control mice (Figure 2H), suggesting that TRPV4EC channels do not influence the efflux of ATP through Panx1EC in response to increase in shear stress. eATP acts through purinergic P2Y2 receptor (P2Y2REC) stimulation to activate TRPV4EC channels
Summary
The pulmonary endothelium exerts a dilatory influence on small, resistance-sized pulmonary arteries (PAs) and thereby lowers pulmonary arterial pressure (PAP). Endothelial signaling mechanisms that control PA contractility remain poorly understood. In this regard, pannexin 1 (Panx1), which is expressed in the pulmonary endothelium and epithelium (Navis et al, 2020), has emerged as a crucial controller of endothelial function (Begandt et al, 2017; Good et al, 2015). The most studied member of the pannexin family, forms a hexameric transmembrane channel at the cell membrane that allows efflux of ATP from the cytosol (Bao et al, 2004; Lohman et al, 2012). Endothelial Panx (Panx1EC) has been linked to inflammation in pulmonary capillaries (Sharma et al, 2018). The physiological roles of Panx1EC in the pulmonary vasculature are largely unknown
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