Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

Figure 4

Effect of TRAIL, NHE, and HIMF on VSMCs. (1) Hypoxia induces TRAIL to combine with TRAIL-R and enhance the expression of insulin-like growth factor-type 1 receptor (IGF1R) through the NF-κB pathway, promoting vascular intimal hyperplasia [125]. (2) HIMF upregulates VEGF and VCAM expressions via PDK1/PI3K/Akt/NF-κB signaling pathway [126]. (3) HIMF regulates the cell cyclin E expression through the PI3K/AKT/mTOR pathway, causing a rapid shift from G0/G1 phase to S phase development in VSMCs [127]. (4) Hypoxia-induced increase in the HIMF expression results in the release of large amounts of [Ca²⁺] from the calcium pool into the cytoplasm [94, 128]. (5) Hypoxia activates the NHE channel, resulting in a decrease in intracellular [H⁺] and an increase in [Na⁺], leading to a rise in pH and VSMC proliferation.