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.