Molecular basis of HPV.
The precise mechanism of HPV remains unclear (Sylvester, Shimoda, Aaronson & Ward, 2012). Published studies indicate that both the sensor and effector mechanisms required for acute HPV are located in pulmonary arterial smooth muscle cells (PASMC) (Bigham & Lee, 2014; Wang, Weigand, Lu, Sylvester, Semenza & Shimoda, 2006; Young, Williams & Thompson, 2019), while endothelial cells (EC) and extracellular matrix cells play an important role in modulating HPV (Dimmeler, Fleming, Fisslthaler, Hermann, Busse & Zeiher, 1999; Fukuroda, Ozaki, Ihara, Ishikawa, Yano & Nishikibe, 1994; Sakao, Tatsumi & Voelkel, 2009; Tian, McKnight & Russell, 1997; Xu, Tan, Tampe, Sanchez, Zeisberg & Zeisberg, 2015). The initial event for HPV is probably a mitochondrial redox signal in response to low PO2 (Dunham-Snary et al., 2017; Peng et al., 2011), then the “O2 sensor“ signals to the “effectors“ leading to smooth muscle contraction. The canonical mechanism of HPV includes PASMC membrane depolarization due to acute hypoxia-induced reduction of K+ channel activity. This subsequently opens voltage-dependent L-type of Ca2+ channels (VDCC) and increases cytosolic free Ca2+ concentration ([Ca2+]cyt) via Ca2+ influx through VDCC. Meanwhile, hypoxia can also directly open receptor-operated Ca2+ channels (ROC), and store-operated Ca2+ channels (SOC), causing an increase in [Ca2+]cyt in PASMC (Dunham-Snary et al., 2017; Luks & Swenson, 2015; Mauban, Remillard & Yuan, 2005; Sylvester, Shimoda, Aaronson & Ward, 2012). Elevated [Ca2+]cyt is a major trigger for PASMC contraction and proliferation (He et al., 2018; Kuhr, Smith, Song, Levitan & Yuan, 2012; Song et al., 2018). Therefore, if mitochondria or the mitochondrial respiratory chain is the O2 sensor in PASMC, the membrane receptors and ion channels and cytosolic Ca2+ are the effectors for HPV.