From the Journal archives: Understanding the mechanism(s) regulating hypoxic pulmonary vasoconstriction: how an early study has led to novel translational approaches

“…Our results showed the MMSE score 4 days after double-lumen bronchial general anesthesia was lower than in the tubeless anesthesia group {30 [28][29][30] vs. 28.5 [27][28][29][30], P=0.047}, and the incidence of cognitive function was higher than that in the SV group (13.3% vs. 3.3%, P>0.05). However, there was no statistical significance between the two groups.…”

“…CO 2 has a complex impact on physiological function and participates in the physiological activities of important organs such as the heart, brain, and lung ( 28 , 29 ). Hypercapnia can improve pulmonary oxygenation ( 30 ), regulate pulmonary compliance and airway resistance ( 31 ), and reduce pulmonary inflammation ( 32 , 33 ). At the same time, it increases coronary blood flow and cardiac output ( 29 , 34 ) and improves myocardial oxygen supply ( 35 ).…”

“…Signaling events downstream of the initial redox changes involve inhibition of oxygen-sensitive potassium channels (voltage-gated K v and TASK-1), activation of Ca 2ϩ channels (voltage-gated Ca 2ϩ channels, transient receptor potential Ca 2ϩ channels), as well as activation of the RhoA/Rho-kinase pathway, all of which have been reviewed expertly before (91). Importantly, all these mechanistic models focus on the pulmonary arterial smooth muscle cell (PASMC) as both the sensor and effector of HPV; that is, oxygen sensing, the transduction of this signal, and the final output of smooth muscle contraction are all held within the PASMC (33). The role of the lung endothelium in the hypoxia-induced signaling cascade that mediates HPV was, on the other hand, long assumed to be largely insignificant.…”

“…The downstream effects of this S1P receptor activation appear to be at least twofold: On the one hand, S1P 2 (via G␣ q/11 ) (45,112) and S1P 4 (via G␣ i ) (34) activate phospholipase C, which catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG), the classical activator of TRPC6 (22). Both, S1P 2 and S1P 4 also signal via G␣ 12/13 to activate RhoA (33,92), which in turn facilitates translocation of TRPC6 to caveolae in a mechanism dependent on phosphatase and tensin homolog (PTEN) (53). Importantly, the role of SphK1, the main source of S1P formation outside the nucleus, and S1P can be mechanistically linked to the endothelial conducted response, in that lung endothelial cells express high levels of SphK1 that markedly exceed those of PASMC (50), that SphK1 translocates upon activation in a Ca 2ϩ -dependent manner to lipid rafts where it binds to the inner leaflet of the plasma membrane (31,75), and that SphK1 activity is amplified by EETs with a time constant that matches the HPV response (43).…”